Detection of a Prethrombotic State in Patients with Hepatocellular Carcinoma, Using a Clot Waveform Analysis.

Although hepatocellular carcinoma (HCC) is frequently associated with thrombosis, it is also associated with liver cirrhosis (LC) which causes hemostatic abnormalities. Therefore, hemostatic abnormalities in patients with HCC were examined using a clot waveform analysis (CWA). Hemostatic abnormalities in 88 samples from HCC patients, 48 samples from LC patients and 153 samples from patients with chronic liver diseases (CH) were examined using a CWA-activated partial thromboplastin time (APTT) and small amount of tissue factor induced FIX activation (sTF/FIXa) assay.

Efficacy of Endoscopic Resection for Rectal Neuroendocrine Tumors Smaller than 15 mm.

Background: Local resection, including endoscopic resection, is recommended for rectal neuroendocrine tumors (NETs) < 15 mm in patients without risk factors for metastasis, though the short- and long-term outcomes are unclear.

Aims: This study investigates the efficacy of endoscopic resection for rectal NETs < 15 mm.

Methods: The short- and long-term outcomes of patients with rectal NETs < 15 mm who underwent endoscopic resection and the outcomes of each endoscopic technique were analyzed.

The gut microbiota composition in patients with right- and left-sided colorectal cancer and after curative colectomy, as analyzed by 16S rRNA gene amplicon sequencing.

Background: Gut pathological microbial imbalance or dysbiosis is closely associated with colorectal cancer. Although there are observable differences in molecular and clinical characteristics between patients with right- and left-sided colon cancer, differences in their gut microbiomes have not been thoroughly investigated. Furthermore, subsequent changes in microbiota status after partial colectomy remain unknown.

Proposal of Quick Diagnostic Criteria for Disseminated Intravascular Coagulation.

Background: The diagnostic criteria for disseminated intravascular coagulation (DIC) vary and are complicated and the cut-off values are different. Simple and quick diagnostic criteria for DIC are required in physicians for critical care.

Material And Methods: Platelet counts, prothrombin time-international normalized ratio (PT-INR) and D-dimer levels were examined in 1293 critical ill patients.

A Clot Waveform Analysis Showing a Hypercoagulable State in Patients with Malignant Neoplasms.

(1) Objective: hypercoagulability in patients with malignant neoplasm were evaluated to examine the relationship with thrombosis. (2) Methods: clot waveform analysis (CWA)-activated partial thromboplastin time (APTT) and CWA-small amount of tissue factor induced FIX activation (sTF/FIXa) assays were performed in 92 patients with malignant neoplasm and the relationship between hypercoagulability and thrombosis was retrospectively examined. (3) Results: The study population included 92 patients with malignant neoplasms.

Evaluation of Biomarkers of Severity in Patients with COVID-19 Infection.

Object: Although many Japanese patients infected with coronavirus disease 2019 (COVID-19) only experience mild symptoms, in some cases a patient's condition deteriorates, resulting in a poor outcome. This study examines the behavior of biomarkers in patients with mild to severe COVID-19.

Methods: The disease severity of 152 COVID-19 patients was classified into mild, moderate I, moderate II, and severe, and the behavior of laboratory biomarkers was examined across these four disease stages.

Fibroblast growth factor receptor modulators employing diamines with reduced phospholipidosis-inducing potential.

SUN13837 (1), a fibroblast growth factor receptor modulator, has been an attractive candidate for treating neurodegenerative diseases. However, one of its metabolites, N-benzyl-4-(methylamino)piperidine (BMP), turned out to possess phospholipidosis-inducing potential (PLIP) in vitro. To obtain SUN13837 analogs with reduced phospholipidosis risk, we replaced BMP with other diamines possessing low PLIP.

Second basic pKa: An overlooked parameter in predicting phospholipidosis-inducing potential of diamines.

In this paper, we present the phospholipidosis-inducing potential (PLIP) of forty fragment-sized diamines derived from N-benzyl-4-(methylamino)piperidine and discuss the relationship between their PLIP and the physicochemical properties. Our results demonstrate that the previously reported methods are not suitable for predicting the PLIP of fragment-sized diamines; the second basic pKa can distinguish PLIP-positive diamines from PLIP-negative diamines more accurately than ClogP or most basic pKa. To the best of our knowledge, this is the first report describing the relationship between PLIP and second basic pKa.

Discovery of a Potent, Selective, and Orally Available MTHFD2 Inhibitor (DS18561882) with in Vivo Antitumor Activity.

We report the discovery of a potent and isozyme-selective MTHFD2 inhibitor, DS18561882 (). Through investigation of the substituents on our tricyclic coumarin scaffold (1,2,3,4-tetrahydrochromeno[3,4-]pyridin-5-one), MTHFD2 inhibitory activity was shown to be elevated by incorporating an amine moiety at the 8-position and a methyl group at the 7-position of the initial lead . X-ray structure analysis revealed that a key interaction for enhanced potency was salt bridge formation between the amine moiety and the diphosphate linker of an NAD cofactor.

Discovery of 1,2,3-triazole-based fibroblast growth factor receptor modulators.

To avoid production of a phospholipidosis-inducing metabolite, we replaced the amide structure of SUN13837 (1) with a 1,2,3-triazole. The resulting 1,2,3-triazole analog of 1 (compound 2) displayed greater neuroprotective activity than 1. Structural modification of 2 yielded compound 10, which showed improved neuroprotective activity and negligible mechanism-based inactivation against CYP3A4.

Structure-Based Design and Synthesis of an Isozyme-Selective MTHFD2 Inhibitor with a Tricyclic Coumarin Scaffold.

Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) plays a key role in one-carbon (1C) metabolism in human mitochondria, and its high expression correlates with poor survival of patients with various types of cancer. An isozyme-selective MTHFD2 inhibitor is highly attractive for potential use in cancer treatment. Herein, we disclose a novel isozyme-selective MTHFD2 inhibitor DS44960156, with a tricyclic coumarin scaffold, which was initially discovered via high-throughput screening (HTS) and improved using structure-based drug design (SBDD).

Changing clinical and molecular characteristics of hepatitis E virus infection in Mie Prefecture, Japan: Disappearance of indigenous subtype 3e strains.

Aim: To evaluate the clinical and molecular characteristics of hepatitis E virus (HEV) infection in Mie Prefecture, Japan, from 2004 through 2018.

Methods: The clinical information of hepatitis E cases was collected from 21 medical institutions in Mie Prefecture. The nucleotide sequences of infecting HEV strains were determined for cases with available serum samples.

Second-line triple therapy in failures with vonoprazan-based triple therapy for eradication of .

Gastric acid inhibition during treatment is important for the eradication of () infection. A novel potassium-competitive acid blocker, vonoprazan (VPZ), has been demonstrated to achieve high eradication rates; however, the efficacy of second-line treatment in failures of VPZ-based triple therapy has not been well studied. The aim of the current study was to determine the efficacy of VPZ in a first-line regimen for eradication, and the efficacy of a second-line regimen using metronidazole (MTZ) in failures with the first-line regimen.

Changes in plasma ghrelin and leptin levels in patients with peptic ulcer and gastritis following eradication of Helicobacter pylori infection.

Background: Helicobacter pylori (H. pylori) infection and eradication therapy have been known to influence gastric ghrelin and leptin secretion, which may lead to weight gain. However, the exact relationship between plasma ghrelin/leptin levels and H.

Comparison of human gut microbiota in control subjects and patients with colorectal carcinoma in adenoma: Terminal restriction fragment length polymorphism and next-generation sequencing analyses.

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in Japan. The etiology of CRC has been linked to numerous factors including genetic mutation, diet, life style, inflammation, and recently, the gut microbiota. However, CRC-associated gut microbiota is still largely unexamined.

Comparison of the gut microbiota composition between obese and non-obese individuals in a Japanese population, as analyzed by terminal restriction fragment length polymorphism and next-generation sequencing.

Background: Obesity has become one of the most serious social problems in developed countries, including Japan. The relationship between the gut microbiota and obesity has recently attracted the attention of many researchers. Although the gut microbiota was long thought to contribute to obesity, the exact association remains largely unknown.

The expression and function of Toll-like receptors 3 and 9 in human colon carcinoma.

Toll-like receptors (TLRs) are pattern-recognition receptors that are important in immune signaling. TLR recognition of various viral components including double-stranded RNA (TLR3) and unmethylated CpG-DNA (TLR9) plays a crucial role in cell survival. However, TLR expression and function in colon carcinoma cells are not well clarified.

Phosphodiesterase 7A inhibitor ASB16165 impairs proliferation of keratinocytes in vitro and in vivo.

Excessive proliferation of epidermal keratinocytes is a typical aspect of chronic skin diseases such as psoriasis. In the present study, the effect of phosphodiesterase 7A (PDE7A) inhibitor ASB16165 on proliferation of keratinocytes was investigated to examine the role of PDE7A in keratinocyte proliferation and the possible therapeutic relevance of PDE7A inhibition in psoriasis. Topical application of ASB16165 inhibited the increase of thickness of skin as well as epidermis in a skin inflammation model induced by repeated painting of 12-O-tetradecanoylphorbol-13-acetate (TPA) in a concentration-dependent manner.

Inhibition of phosphodiesterase 7A ameliorates Concanavalin A-induced hepatitis in mice.

An intravenous injection of Concanavalin A (Con A) elevated the serum level of alanine aminotransferase (ALT) activity, a marker for liver damage, and an oral administration of PDE7A inhibitor SUN11817 suppressed the increase of ALT activity in a dose-dependent manner. Histological analysis revealed that Con A injection caused extensive liver damage, and that the SUN11817 treatment improved the degenerative change in the liver. In addition, SUN11817 inhibited not only the production of IL-4 and TNF-alpha in the Con A-induced hepatitis model but also that in vitro by murine splenocytes stimulated with alpha-galactosylceramide, an activator specific for NKT cells.

Phosphodiesterase 7A inhibitor ASB16165 suppresses proliferation and cytokine production of NKT cells.

A possible involvement of phosphodiesterase 7A (PDE7A) in proliferation and function of NKT cells was examined using ASB16165, a selective inhibitor for PDE7A. Stimulation of isolated murine NKT cells with anti-CD3 antibody plus IL-2 induced not only cell proliferation but production of cytokines including IFN-gamma, TNF-alpha, IL-17 and IL-22. ASB16165 significantly inhibited the CD3/IL-2-stimulated cell proliferation and production of all the cytokines examined.

ASB16165, a phosphodiesterase 7A inhibitor, reduces cutaneous TNF-alpha level and ameliorates skin edema in phorbol ester 12-O-tetradecanoylphorbol-13-acetate-induced skin inflammation model in mice.

Possible role of phosphodiesterase 7A (PDE7A) in skin inflammation was examined using ASB16165, a specific inhibitor for PDE7A. Epicutaneous application of phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse ear resulted in induction of skin edema, and topical treatment with ASB16165 inhibited the induction of skin edema in a dose-dependent manner. The TPA challenge also increased the level of TNF-alpha at the application site, and the ASB16165 treatment reduced the TNF-alpha level in the skin.

ASB16165, a novel inhibitor for phosphodiesterase 7A (PDE7A), suppresses IL-12-induced IFN-gamma production by mouse activated T lymphocytes.

Phosphodiesterase 7A (PDE7A) has been suggested to be involved in activation of T lymphocytes. In the present study, a possible involvement of PDE7A in function of preactivated T cells (i.e.

Effect of phosphodiesterase 7 inhibitor ASB16165 on development and function of cytotoxic T lymphocyte.

In the present study, possible role of phosphodiesterase 7 (PDE7) in development and function of cytotoxic T lymphocyte (CTL) was examined using ASB16165, a specific inhibitor for PDE7. ASB16165 inhibited generation of CTL activity in mixed lymphocyte reaction (MLR), in which splenocytes from C57BL/6N mice were stimulated with those from BALB/c mice. Flow cytometric analysis revealed that ASB16165 suppressed induction of activated CD4+ as well as CD8+ T cells in MLR.

Vitamin K analog (compound 5) induces apoptosis in human hepatocellular carcinoma independent of the caspase pathway.

A systemic vitamin K analog, compound 5 (Cpd 5), possesses the ability to inhibit cell growth of tumor cells. Therefore, we investigated the effect of Cpd 5 in human hepatocellular carcinoma (HCC) cell lines and evaluated its role in apoptosis. Human HCC cell lines were cultured and treated with Cpd 5.