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Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Nonalcoholic steatohepatitis (NASH) is an advanced form of NAFLD can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Recently, the prognosis of NAFLD/NASH has been reported to be dependent on liver fibrosis degree. Liver biopsy remains the gold standard, but it has several issues that must be addressed, including its invasiveness, cost, and inter-observer diagnosis variability. To solve these issues, a variety of noninvasive tests (NITs) have been in development for the assessment of NAFLD progression, including blood biomarkers and imaging methods, although the use of NITs varies around the world. The aim of the Japan NASH NIT (JANIT) Forum organized in 2020 is to advance the development of various NITs to assess disease severity and/or response to treatment in NAFLD patients from a scientific perspective through multi-stakeholder dialogue with open innovation, including clinicians with expertise in NAFLD/NASH, companies that develop medical devices and biomarkers, and professionals in the pharmaceutical industry. In addition to conventional NITs, artificial intelligence will soon be deployed in many areas of the NAFLD landscape. To discuss the characteristics of each NIT, we conducted a SWOT (strengths, weaknesses, opportunities, and threats) analysis in this study with the 36 JANIT Forum members (16 physicians and 20 company representatives). Based on this SWOT analysis, the JANIT Forum identified currently available NITs able to accurately select NAFLD patients at high risk of NASH for HCC surveillance/therapeutic intervention and evaluate the effectiveness of therapeutic interventions., (© 2022. The Author(s).)

Background: mTOR is a genetically conserved serine/threonine protein kinase, which controls cell growth, proliferation, and survival. A multifunctional protein CAD, catalyzing the initial three steps in de novo pyrimidine synthesis, is regulated by the phosphorylation reaction with different protein kinases, but the relationship with mTOR protein kinase has not been known., Results: CAD was recovered as a binding protein with mLST8, a component of the mTOR complexes, from HEK293 cells transfected with the FLAG-mLST8 vector. Association of these two proteins was confirmed by the co-immuoprecipitaiton followed by immunoblot analysis of transfected myc-CAD and FLAG-mLST8 as well as that of the endogenous proteins in the cells. Analysis using mutant constructs suggested that CAD has more than one region for the binding with mLST8, and that mLST8 recognizes CAD and mTOR in distinct ways. The CAD enzymatic activity decreased in the cells depleted of amino acids and serum, in which the mTOR activity is suppressed., Conclusion: The results obtained indicate that mLST8 bridges between CAD and mTOR, and plays a role in the signaling mechanism where CAD is regulated in the mTOR pathway through the association with mLST8.

The target of rapamycin (Tor) protein plays central roles in cell growth. Rapamycin inhibits cell growth and promotes cell cycle arrest at G1 (G0). However, little is known about whether Tor is involved in other stages of the cell division cycle. Here we report that the rapamycin-sensitive Tor complex 1 (TORC1) is involved in G2/M transition in S. cerevisiae. Strains carrying a temperature-sensitive allele of KOG1 (kog1-105) encoding an essential component of TORC1, as well as yeast cell treated with rapamycin show mitotic delay with prolonged G2. Overexpression of Cdc5, the yeast polo-like kinase, rescues the growth defect of kog1-105, and in turn, Cdc5 activity is attenuated in kog1-105 cells. The TORC1-Type2A phosphatase pathway mediates nucleocytoplasmic transport of Cdc5, which is prerequisite for its proper localization and function. The C-terminal polo-box domain of Cdc5 has an inhibitory role in nuclear translocation. Taken together, our results indicate a novel function of Tor in the regulation of cell cycle and proliferation.

Three common variants of soluble cytoplasmic L-alanine:2-oxoglutarate aminotransferase (ALT, EC 2.6.1.2), sALT 1, 2-1 and 2, were isolated from normal human liver, and characterized by electrophoretic and kinetic analyses. The isoelectric point of sALT 1 was pH 6.45. sALT 2-1 was focused into three bands with pl 6.1, 6.2 and 6.45; sALT was focused into one band with pl 6.1. The electrophoretic mobilities of sALTs altered to the fast beta-globulin fraction after aging or papain treatment. Ammonia was produced during the latter, and the altered migration was considered to be caused by deamidation of sALT. The relative molecular mass of each of the enzymes was 110,000. Minor differences in the apparent Km values among the multiple forms for both L-alanine and 2-oxoglutarate were observed after incubation with 100 mumol/L of pyridoxal phosphate (PALP). PALP stimulation of the enzyme activities was also different. sALT 1 was more stable than sALT 2-1 and 2 after heat and urea treatments. In human sera from 1065 adult Japanese, sALT 2-1, a heterozygote form of sALT 1 and 2, was dominant.

Multicenter clinical trial or TMS-19-Q.O tablet was performed to evaluate the usefulness in oral surgery. The results obtained were as follows: Clinical efficacy was assessed by clinical points. The patients entered into the trial were 77 cases with periodontitis, 23 with pericoronitis, 92 with osteitis of jaw and 18 with other infections, and the each effective rates were 80.5, 60.9, 83.7 and 72.2%, respectively. Overall effective rate was 79.0%. Isolation frequency of organisms were 33.8% in periodontitis, 34.8% in osteitis of jaw and 17.4% in pericoronitis. Bacteria isolated were aerobic organisms (63.1%) and anaerobic organisms (36.9%). TMS-19-Q.O tablet was well tolerated, and no adverse reaction was observed.

The origin of an atypical creatine kinase (CK, ATP:creatine N-phosphotransferase, EC 2.7,3.2) migrating cathodic to the MM position found in the serum of a cancer patient was studied. The electrophoretic mobility of the atypical CK is similar to that of the fast-moving cathodal mitochondrial CK. The relative molecular mass was estimated to be approximately 350000, and was similar to that of the fast-moving cathodal mitochondrial CK. The atypical CK reacted with anti-human mitochondrial CK antibody. It is therefore suggested that the atypical CK is of mitochondrial origin. After incubation in 2 mol/l urea, the enzyme was converted into a new form migrating to the MM position. The conversion was observed in liver mitochondrial CK but not heart mitochondrial CK. The residual CK activity after heating at 56 degrees C for 60 s was 77%, and the apparent Km value for creatine phosphate at 30 degrees C was about 0.27 mmol for the atypical CK. These characteristics were very similar to those of the liver mitochondrial CK, because the data from the enzyme determined at the same time were 75% for residual enzyme activity to heat, and 0.24 mmol for apparent Km value. Therefore liver mitochondria are suggested to be the source of the atypical CK.

Mitochondrial creatine kinases (CKs, ATP:creatine N-phosphotransferases, EC 2.7.3.2) were isolated from normal human heart and liver, and their characteristics were compared. The electrophoretic patterns of the extracted enzymes exhibited two forms both migrating cathodic to CK-MM. The fast-moving cathodal form is the major form and the slow-moving cathodal form is the minor one. Incubation of the heart mitochondrial CK at 37 degrees C in normal human serum for 7 h and of the liver mitochondrial CK at 26 degrees C for 1 h in 2 mol/l urea, converted the fast-moving form into the slow-moving one, and finally into a third form migrating in the MM position. The relative molecular masses were estimated to be approximately 350,000 for the major form, and 80,000 for the minor and the third forms. The electrophoretic mobility and molecular weight of the third form were identical to those of the CK-MM; however, the third form was distinguished from CK-MM by its different antigenicity. Thus, three forms were ultimately recognized as mitochondrial CKs by electrophoretic mobilities and molecular weights. The liver mitochondrial CK reacted with anti-human heart mitochondrial CK antibody, thus these two isoenzymes could not be discriminated by their antigenicities. The liver mitochondrial CK was more stable to heat and had higher apparent affinity for creatine phosphate than the heart mitochondrial CK.

A new creatine kinase (CK, ATP: creatine N-phosphotransferase, EC 2.7.3.2) band was found in mitochondrial extracts prepared from malignant liver tissue. By agar gel electrophoresis the new band (CKmLT) migrated between CK-MM and a sample application point. The CK band was not found in mitochondrial extracts of normal liver, cytosolic extracts of normal and malignant liver homogenates. We thus presume that the origin of CKmLT is from mitochondria of malignant liver tumors. CKmLT reacted with anti-mitochondrial CK antibodies so that its antigenicity was similar to that of mitochondrial CK. Physico-chemical characteristics were similar to those of the polymeric form of the normal liver mitochondrial CK (CKmL1); i.e. relative molecular mass (320 000 to 350 000), heat stability, and the behavior in 2 mol/l urea. CKmLT migrated to the CKmL1 and the MM position after long-term storage at -20 degrees C. CKmLT did not demonstrate affinity to concanavalin A, and there was no significant change in the electrophoretic mobility of CKmLT following neuraminidase treatment.

Sera from 167 patients with malignant tumor were examined with regard to mitochondrial creatine kinase (ATP: creatine N-phosphotransferase, EC 2.7.3.2, CK). The CK (CKm) was detected in 66 cases (40%), in 42 of 96 men and in 24 of 71 women. Seventeen patients had hepatic carcinomas and 14 gastric carcinoma. CKm was also present in sera from patients with malignancy of the lung, the mammary gland etc. In the CKm positive group, about 85% had metastatic and/or infiltrating malignancy, and about 90% were undergoing chemotherapy. The figures resembled those in the CKm negative group. Mortality rates in the CKm positive group were 1.7 times higher than in the CKm negative group. CKm may be a marker of some biological factors leading to and/or resulting from a poor prognosis and not simply of primary or metastatic tumors. Most of the total serum CK activities in the CKm positive group were within normal limits. CKm activities in the gastric carcinoma group were higher than those in other groups, particularly in comparison to the liver carcinoma group.

Three electrophoretically atypical creatine kinase (CK) bands were found simultaneously in the serum of a patient with terminal carcinoma of the colon. The atypical CKs were found at the cathodal side of CK-MB (CK-X1), at a sample application point (CK-X2), and at the anodal side of CK-MM (CK-X3) on agar plates. Our data seemed to suggest that CK-X1 was predominantly a CK-IgA/beta-lipoprotein complex, CK-X3 was a CK-IgG complex, and CK-X2 was macromolecular, different from both CK-X1 and CK-X3. The light chains of IgA and IgG were both of the lambda type. All native isoenzymes comprising these atypical CKs were identified as MM type. There was no change of the electrophoretic pattern of serum CK isoenzymes throughout the course of the study.

Detailed oro-maxillofacial studies using dental casts, pantomograms and cephalograms were performed in 28 patients with Turner's syndrome and compared statistically to the results from 23 normal short children. Small tooth crown size, short tooth roots and advanced dental age were characteristic of patients with Turner's syndrome. However, the incidence of peg shaped teeth, malocclusion, high arched palate and congenital anodontia were not characteristic of patients with Turner's syndrome. The coronal arch width (C.A.W.) and basal arch width (B.A.W.) were greater and the coronal arch length (C.A.L.) and basal arch length (B.A.L.) were less in patient's with Turner's syndrome. These data indicate underdevelopment of the maxilla in the forward direction forming the wide-, flat-shaped facial characteristic of patients with Turner's syndrome.