A New Deep State-Space Analysis Framework for Patient Latent State Estimation and Classification from EHR Time Series Data

Many diseases, including cancer and chronic conditions, require extended treatment periods and long-term strategies. Machine learning and AI research focusing on electronic health records (EHRs) have emerged to address this need. Effective treatment strategies involve more than capturing sequential changes in patient test values. It requires an explainable and clinically interpretable model by capturing the patient's internal state over time. In this study, we propose the "deep state-space analysis framework," using time-series unsupervised learning of EHRs with a deep state-space model. This framework enables learning, visualizing, and clustering of temporal changes in patient latent states related to disease progression. We evaluated our framework using time-series laboratory data from 12,695 cancer patients. By estimating latent states, we successfully discover latent states related to prognosis. By visualization and cluster analysis, the temporal transition of patient status and test items during state transitions characteristic of each anticancer drug were identified. Our framework surpasses existing methods in capturing interpretable latent space. It can be expected to enhance our comprehension of disease progression from EHRs, aiding treatment adjustments and prognostic determinations.Comment: 21 pages, 6 figure

What Are the Precursor and Early Lesions of Peripheral Intrahepatic Cholangiocarcinoma?

Cholangiocarcinoma (CC) is divided into distal, perihilar, and intrahepatic CCs (ICCS), and are further subdivided into large bile duct ICC and peripheral ICC. In distal and perihilar CC and large duct ICC, biliary intraepithelial neoplasm (BilIN) and intraductal papillary neoplasm (IPN) have been proposed as precursor lesions. Peripheral ICC, bile duct adenoma (BDA), biliary adenofibroma (BAF), and von Meyenburg complexes (VMCs) are reportedly followed by development of ICCs. Herein, we surveyed these candidate precursor lesions in the background liver of 37 cases of peripheral ICC and controls (perihilar CC, 34 cases; hepatocellular carcinoma, 34 cases and combined hepatocellular cholangiocarcinoma, 25 cases). In the background liver of peripheral ICC, BDA and BAF were not found, but there were not infrequently foci of BDA-like lesions and atypical bile duct lesions involving small bile ducts (32.4% and 10.8%, resp.). VMCs were equally found in peripheral CCs and also control CCs. In conclusion, BDA, BAF, and VMCs are a possible precursor lesion of a minority of peripheral CCs, and BDA-like lesions and atypical bile duct lesions involving small bile ducts may also be related to the development of peripheral ICC. Further pathologic studies on these lesions are warranted for analysis of development of peripheral ICCs

A Case of Hypereosinophilia-Associated Multiple Mass Lesions of Liver Showing Non-Granulomatous Eosinophilic Hepatic Necrosis

Hypereosinophilic syndrome (HES) is defi ned by elevation more than 1.5×109/L of presence of a peripheral blood count, evidence of organ involvement, and exclusion of secondary eosinophilia such as allergic, vasculitis, drugs, or parasite infection and also clonal eosinophilia. We present the HES case with hepatic involvement. The patient is 70-year-old male. He complained fever and back pain. Blood examination showed marked peripheral eosinophilia, elevation of transaminase and biliary enzymes. Multiple irregular mass lesions of the liver were pointed out by CT and MRI. The liver biopsy was done for differentiation from malignancy. In parenchyma, hepatic necrotic lesion was observed accompanying severe eosinophilic infi ltration with Charcot-Leyden’s crystals. There was granulomatous reaction. He was diagnosed as HES and got recovery due to steroid therapy. From the review of HES article, the hepatic histology is categorized into four types as below: 1) cholangitis type; 2) chronic active hepatitis type; 3) vasculopathic type, 4) hepatic necrosis type. Our case is classifi ed in hepatic necrosis type. This type seems to be important to distinguish malignant tumor and also visceral larva migrans by liver biopsy

Histone deacetylase inhibitor (SAHA) and repression of EZH2 synergistically inhibit proliferation of gallbladder carcinoma

医薬保健研究域医学系Polycomb group protein EZH2, frequently overexpressed in malignant tumors, is the catalytic subunit of polycomb repressive complex 2 (PRC2). PRC2 interacts with HDACs in transcriptional silencing and relates to tumor suppressor loss. We examined the expression of HDAC isoforms (HDAC 1 and 2) and EZH2, and evaluated the possible use of HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) and EZH2 repressor for gallbladder carcinoma. We used 48 surgically resected gallbladders and cultures of human gallbladder epithelial cells (HGECs), gallbladder carcinoma (TGBC2TKB), and cholangiocarcinoma (HuCCT-1 and TFK-1) cell lines for examination. Immunohistochemically, EZH2 was overexpressed in gallbladder carcinoma, especially poorly differentiated carcinoma, but not in normal epithelium. In contrast, HDAC1/2 were expressed in both carcinoma and normal epithelium in vivo. This pattern was verified in cultured cells; EZH2 was highly expressed only in TGBC2TKB, whereas HDAC1/2 were expressed in HGECs and TGBC2TKB. Interestingly, SAHA treatment caused significant cell number decline in three carcinoma cells, and this effect was synergized with EZH2 siRNA treatment; however, HGECs were resistant to SAHA. In TGBC2TKB cells, the expression of EZH2 and HDAC1/2 were decreased by SAHA treatment, and p16INK4a, E-cadherin, and p21were simultaneously activated; however, no such findings were obtained in HGECs, suggesting that the effect of SAHA depends on the EZH2-mediated tumor suppressor loss. In conclusion, this study suggests a possible mechanism by which carcinoma cells but not normal cells are sensitive to SAHA and indicates the efficacy of this new anticancer agent in combination with EZH2 repression in gallbladder carcinoma. © 2009 Japanese Cancer Association

Local balance of transforming growth factor-β1 secreted from cholangiocarcinoma cells and stromal-derived factor-1 secreted from stromal fibroblasts is a factor involved in invasion of cholangiocarcinoma

金沢大学大学院医学系研究科がん細胞学Tumor-stromal interactions are important for the progression of malignant tumors. The purpose of the present study was to examine interactions of cholangiocarcinoma (CC) cells and stromal fibroblasts with respect to stromal-derived factor-1 (SDF-1) and transforming growth factor (TGF)-β1. Two cell lines of CC (HuCCT-1 and CCKS-1) and WI-38 fibroblast cell line were used for cell culture, and 12 CC tissue specimens for immunohistochemical studies. Invasion of CC cells was increased significantly by the supernatant from fibroblast cultures, but not by the supernatant from fibroblasts cocultured with CC cells. Expression of SDF-1 in cultured fibroblasts was downregulated by TGF-β1 treatment, and coculture with CC cells and anti-TGF-β1 neutralizing antibody restored the decreased SDF-1 expression, suggesting that TGF-β1 secreted from CC cells might have reduced the expression of SDF-1 by fibroblasts and might have reduced the increased invasion of CC cells induced by the supernatant from fibroblasts. Immunohistochemical expression of TGF-β1 in CC cells was focal or negative and that of SDF-1 was evident in stromal fibroblasts at the invasive front of CC. In conclusion, local mutual influence of TGF-β1 secreted from carcinoma cells and SDF-1 expressed by stromal fibroblasts may be involved in invasion of CC cells. © 2006 Japanese Society of Pathology

Afferent signalling from the acid-challenged rat stomach is inhibited and gastric acid elimination is enhanced by lafutidine

<p>Abstract</p> <p>Background</p> <p>Lafutidine is a histamine H₂receptor antagonist, the gastroprotective effect of which is related to its antisecretory activity and its ability to activate a sensory neuron-dependent mechanism of defence. The present study investigated whether intragastric administration of lafutidine (10 and 30 mg/kg) modifies vagal afferent signalling, mucosal injury, intragastric acidity and gastric emptying after gastric acid challenge.</p> <p>Methods</p> <p>Adult rats were treated with vehicle, lafutidine (10 – 30 mg/kg) or cimetidine (10 mg/kg), and 30 min later their stomachs were exposed to exogenous HCl (0.25 M). During the period of 2 h post-HCl, intragastric pH, gastric volume, gastric acidity and extent of macroscopic gastric mucosal injury were determined and the activation of neurons in the brainstem was visualized by c-Fos immunocytochemistry.</p> <p>Results</p> <p>Gastric acid challenge enhanced the expression of c-Fos in the nucleus tractus solitarii but caused only minimal damage to the gastric mucosa. Lafutidine reduced the HCl-evoked expression of c-Fos in the NTS and elevated the intragastric pH following intragastric administration of excess HCl. Further analysis showed that the gastroprotective effect of lafutidine against excess acid was delayed and went in parallel with facilitation of gastric emptying, measured indirectly via gastric volume changes, and a reduction of gastric acidity. The H₂receptor antagonist cimetidine had similar but weaker effects.</p> <p>Conclusion</p> <p>These observations indicate that lafutidine inhibits the vagal afferent signalling of a gastric acid insult, which may reflect an inhibitory action on acid-induced gastric pain. The ability of lafutidine to decrease intragastric acidity following exposure to excess HCl cannot be explained by its antisecretory activity but appears to reflect dilution and/or emptying of the acid load into the duodenum. This profile of actions emphasizes the notion that H₂receptor antagonists can protect the gastric mucosa from acid injury independently of their ability to suppress gastric acid secretion.</p

Evaluation of a new histologic staging and grading system for primary biliary cirrhosis in comparison with classical systems

Recently, our research team proposed a new histologic staging and grading system for primary biliary cirrhosis (PBC) that takes into account necroinflammatory activity and histologic heterogeneity. The present study aimed to confirm the usefulness of the new evaluation system. A total of 152 liver biopsy specimens and clinical data (including outcomes in patients with PBC before treatment with ursodeoxycholic acid) were analyzed with respect to the new system. Staging was evaluated on the basis of 3 histologic components (fibrosis, bile duct loss, and deposition of orcein-positive granules), and grading was assessed on the basis of chronic cholangitis activity and hepatitis activity. Concurrently, the classical systems, that is, the Scheuer and Ludwig staging systems, were also assessed and compared with our new system. PBC cases showed different distributions in each stage of the 3 systems. The new staging and grading system reflected liver dysfunctions before specific treatment. This was on a par with the results obtained using the classical systems. Development of cirrhosis-related conditions correlated well with the new staging system compared with the 2 classical staging systems, and in particular, the amount of deposition of orcein-positive granules could reflect development of cirrhosis-related conditions (scores 0-1 versus scores 2-3 groups, P < .0001). In conclusion, the new PBC staging system was demonstrated to reflect clinicolaboratory features, and its progression was associated with the development of cirrhosis-related conditions. © 2013 Elsevier Inc. All rights reserved

Gravitational Wave Physics and Astronomy in the nascent era

The detections of gravitational waves (GW) by the LIGO/Virgo collaborations provide various possibilities for both physics and astronomy. We are quite sure that GW observations will develop a lot, both in precision and in number, thanks to the continuous work on the improvement of detectors, including the expected new detector, KAGRA, and the planned detector, LIGO-India. On this occasion, we review the fundamental outcomes and prospects of gravitational wave physics and astronomy. We survey the development, focusing on representative sources of gravitational waves: binary black holes, binary neutron stars, and supernovae. We also summarize the role of gravitational wave observations as a probe of new physics