α-L-iduronidase fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa) for mucopolysaccharidosis type I: A phase 1/2 trial.

Mucopolysaccharidosis type I (MPS I) causes systemic accumulation of glycosaminoglycans due to a genetic deficiency of α-L-iduronidase (IDUA), which results in progressive systemic symptoms affecting multiple organs, including the central nervous system (CNS). Because the blood-brain barrier (BBB) prevents enzymes from reaching the brain, enzyme replacement therapy is effective only against the somatic symptoms. Hematopoietic stem cell transplantation can address the CNS symptoms, but the risk of complications limits its applicability. We have developed a novel genetically modified protein consisting of IDUA fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa; JR-171), which has been shown in nonclinical studies to be distributed to major organs, including the brain, bringing about systemic reductions in heparan sulfate (HS) and dermatan sulfate concentrations. Subsequently, a first-in-human study was conducted to evaluate the safety, pharmacokinetics, and exploratory efficacy of JR-171 in 18 patients with MPS I. No notable safety issues were observed. Plasma drug concentration increased dose dependently and reached its maximum approximately 4 h after the end of drug administration. Decreased HS in the cerebrospinal fluid suggested successful delivery of JR-171 across the BBB, while suppressed urine and serum concentrations of the substrates indicated that its somatic efficacy was comparable to that of laronidase.

Tofogliflozin long-term effects on atherosclerosis progression and major clinical parameters in patients with type 2 diabetes mellitus lacking a history of cardiovascular disease: a 2-year extension study of the UTOPIA trial.

BACKGROUND: This study aimed to assess the long-term effects of tofogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on atherosclerosis progression and major clinical parameters in patients with type 2 diabetes lacking an apparent history of cardiovascular disease. METHODS: This was a prospective observational 2-year extension study of the "Using TOfogliflozin for Possible better Intervention against Atherosclerosis for type 2 diabetes patients (UTOPIA)" trial, a 2-year randomized intervention study. The primary endpoints represented changes in the carotid intima-media thickness (IMT). Secondary endpoints included brachial-ankle pulse wave velocity (baPWV) and biomarkers for glucose metabolism, lipid metabolism, renal function, and cardiovascular risks. RESULTS: The mean IMT of the common carotid artery (IMT-CCA) significantly decreased in both the tofogliflozin (- 0.067 mm, standard error 0.009, p < 0.001) and conventional treatment groups (- 0.080 mm, SE 0.009, p < 0.001) throughout the follow-up period; however, no significant intergroup differences in the changes (0.013 mm, 95% confidence interval (CI) - 0.012 to 0.037, p = 0.32) were observed in a mixed-effects model for repeated measures. baPWV significantly increased in the conventional treatment group (82.7 ± 210.3 cm/s, p = 0.008) but not in the tofogliflozin group (- 17.5 ± 221.3 cm/s, p = 0.54), resulting in a significant intergroup difference in changes (- 100.2 cm/s, 95% CI - 182.8 to - 17.5, p = 0.018). Compared to the conventional treatment group, tofogliflozin significantly improved the hemoglobin A1c and high-density lipoprotein cholesterol levels, body mass index, abdominal circumference, and systolic blood pressure. The frequencies of total and serious adverse events did not vary significantly between the groups. CONCLUSIONS: Tofogliflozin was not associated with improved inhibition of carotid wall thickening but exerted long-term positive effects on various cardiovascular risk factors and baPWV while showing a good safety profile.

Visceral fat area is a better indicator of surgical outcomes after laparoscopic gastrectomy for cancer than the body mass index: a propensity score-matched analysis.

BACKGROUND: The number of overweight gastric cancer patients who are undergoing laparoscopic gastrectomy (LG) has increased in Japan. However, the relationship between obesity and surgical outcomes of LG remains unclear. Therefore, this study aimed to evaluate the effect of visceral fat area (VFA) on surgical outcomes of LG for gastric cancer compared to the body mass index (BMI). METHODS: This study was a retrospective, cohort study that included 587 patients who underwent LG in our institution between January 2015 and December 2019. The patients were divided into two groups according to VFA (< 100 cm2 and ≥ 100 cm2) and BMI (< 25 kg/m2 and ≥ 25 kg/m2) values, respectively. Surgical outcomes and postoperative complications were compared between the low and high groups for each VFA and BMI value. Propensity score matching was used to minimize potential selection bias. RESULTS: After propensity score matching, 144 pairs of patients in the VFA group and 82 pairs of patients in the BMI group were extracted. Operative time (p = 0.003), intraoperative blood loss (p = 0.0006), and CRP levels on postoperative day 1 (p = 0.002) and on postoperative day 3 (p = 0.004) were significantly higher in the high-VFA group than in the low-VFA group. However, these surgical outcomes were not significantly different between the high-BMI and low-BMI groups. There was no strong correlation between VFA and BMI (R2 = 0.64). There were no significant differences in postoperative complications between the high and low groups for both VFA and BMI values. On multivariate analysis, high VFA was an independent predictor of operative time, but it was not significantly associated with the incidence of postoperative complications. CONCLUSION: VFA is a better indicator of longer operative time than BMI. However, increased VFA did not affect postoperative complications.

Effect of tofogliflozin on arterial stiffness in patients with type 2 diabetes: prespecified sub-analysis of the prospective, randomized, open-label, parallel-group comparative UTOPIA trial.

BACKGROUND: Tofogliflozin, an SGLT2 inhibitor, is associated with favorable metabolic effects, including improved glycemic control and serum lipid profile and decreased body weight, visceral adipose tissue, and blood pressure (BP). This study evaluated the effects of tofogliflozin on the brachial-ankle pulse wave velocity (baPWV) in patients with type 2 diabetes (T2DM) without a history of apparent cardiovascular disease. METHODS: The using tofogliflozin for possible better intervention against atherosclerosis for type 2 diabetes patients (UTOPIA) trial is a prospective, randomized, open-label, multicenter, parallel-group, comparative study. As one of the prespecified secondary outcomes, changes in baPWV over 104 weeks were evaluated in 154 individuals (80 in the tofogliflozin group and 74 in the conventional treatment group) who completed baPWV measurement at baseline. RESULTS: In a mixed-effects model, the progression in the right, left, and mean baPWV over 104 weeks was significantly attenuated with tofogliflozin compared to that with conventional treatment (- 109.3 [- 184.3, - 34.3] (mean change [95% CI] cm/s, p = 0.005; - 98.3 [- 172.6, - 24.1] cm/s, p = 0.010; - 104.7 [- 177.0, - 32.4] cm/s, p = 0.005, respectively). Similar findings were obtained even after adjusting the mixed-effects models for traditional cardiovascular risk factors, including body mass index (BMI), glycated hemoglobin (HbA1c), total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglyceride, systolic blood pressure (SBP), hypertension, smoking, and/or administration of drugs, including hypoglycemic agents, antihypertensive agents, statins, and anti-platelets, at baseline. The findings of the analysis of covariance (ANCOVA) models, which included the treatment group, baseline baPWV, and traditional cardiovascular risk factors, resembled those generated by the mixed-effects models. CONCLUSIONS: Tofogliflozin significantly inhibited the increased baPWV in patients with T2DM without a history of apparent cardiovascular disease, suggesting that tofogliflozin suppressed the progression of arterial stiffness. Trial Registration UMIN000017607. Registered 18 May 2015. ( https://www.umin.ac.jp/icdr/index.html ).

Pharmacokinetics and pharmacodynamics of JR-051, a biosimilar of agalsidase beta, in healthy adults and patients with Fabry disease: Phase I and II/III clinical studies.

Fabry disease is a rare X-linked lysosomal disease, in which mutations in the gene encoding α-galactosidase A result in progressive cellular accumulation of globotriaosylceramide (GL-3) in various organs including the skin, kidney, and heart, often leading to life-threatening conditions. Enzyme replacement therapy is currently the standard therapy for the disease, to which two α-galactosidase A formulations have been approved: agalsidase α (Replagal®, Shire) and agalsidase ß (Fabrazyme®, Sanofi). We have recently developed a biosimilar of agalsidase ß, JR-051, and investigated its pharmacokinetics and pharmacodynamics to assess its bioequivalence to agalsidase ß. In a randomized phase I study, healthy adult male volunteers were treated with JR-051 or agalsidase ß and the pharmacokinetics of the drugs were compared. The ratio of geometric means (90% confidence interval [CI]) of the AUC0-24 and Cmax for JR-051 over agalsidase ß were 0.91 (0.8294, 1.0082) and 0.90 (0.7992, 1.0125), respectively. In a 52-week, single-arm, phase II/III study, patients with Fabry disease switched therapy from agalsidase ß to JR-051 to evaluate its pharmacodynamics. The mean (95% CI) plasma GL-3 concentrations at weeks 26 and 52 relative to pre-JR-051 administration were 1.03 (0.91, 1.15) and 0.96 (0.86, 1.06), respectively, which were within the pre-determined bioequivalence acceptance range (0.70, 1.43). The mean (95% CI) plasma globotriaosylsphingosine (lyso-GL-3) concentrations at weeks 26 and 52 relative to pre-JR-051 administration were 1.07 (0.92, 1.23) and 1.13 (1.03, 1.22), respectively. Estimated glomerular filtration rate and left ventricular mass index, as renal and cardiac function indicators, showed no notable changes from baseline throughout the study period, and no new safety concerns were identified. In conclusion, these studies demonstrated bioequivalence of JR-051 to agalsidase ß in terms of its pharmacokinetics and pharmacodynamics. JR-051 offers a potential new treatment option for patients with Fabry disease.

Tofogliflozin does not delay progression of carotid atherosclerosis in patients with type 2 diabetes: a prospective, randomized, open-label, parallel-group comparative study.

BACKGROUND: This study aimed to investigate the preventive effects of tofogliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, on atherosclerosis progression in type 2 diabetes (T2DM) patients without apparent cardiovascular disease (CVD) by monitoring carotid intima-media thickness (IMT). METHODS: This prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group, comparative study included 340 subjects with T2DM and no history of apparent CVD recruited at 24 clinical units. Subjects were randomly allocated to either the tofogliflozin treatment group (n = 169) or conventional treatment group using drugs other than SGLT2 inhibitors (n = 171). Primary outcomes were changes in mean and maximum common carotid IMT measured by echography during a 104-week treatment period. RESULTS: In a mixed-effects model for repeated measures, the mean IMT of the common carotid artery (mean-IMT-CCA), along with the right and left maximum IMT of the CCA (max-IMT-CCA), significantly declined in both the tofogliflozin (- 0.132 mm, SE 0.007; - 0.163 mm, SE 0.013; - 0.170 mm, SE 0.020, respectively) and the control group (- 0.140 mm, SE 0.006; - 0.190 mm, SE 0.012; - 0.190 mm, SE 0.020, respectively). Furthermore, the tofogliflozin and the conventional treatment group did not significantly differ in the progression of the mean-IMT-CCA (mean change (95% CI) 0.008 (- 0.009, 0.025) mm, P = 0.34), along with the right (mean change (95% CI) 0.027 (- 0.005, 0.059) mm, P = 0.10) and the left max-IMT-CCA (mean change (95% CI) 0.020 (- 0.030, 0.070), P = 0.43). Similar findings were obtained even after adjusting for traditional CV risk factors and/or administration of drugs at baseline. Relative to the control treatment effects, tofogliflozin significantly reduced the HbA1c, blood glucose level, body weight/body mass index, abdominal circumference, and systolic blood pressure, and significantly increased the HDL-C. The total and serious adverse events incidences did not significantly vary between the treatment groups. CONCLUSIONS/INTERPRETATION: No IMT changes were observed between the tofogliflozin and the conventional treatment groups. However, tofogliflozin is a safe and effective treatment option for managing primary CVD risk factors in this population. Clinical Trial Registration UMIN000017607 ( https://www.umin.ac.jp/icdr/index.html ).

The crossover technique for intracorporeal esophagojejunostomy following laparoscopic total gastrectomy: a simple and safe technique using a linear stapler and two barbed sutures.

BACKGROUND: Totally laparoscopic gastrectomy (LG) is preferred over open gastrectomy because it allows safe anastomosis, a small wound, and early bowel recovery. However, esophagojejunostomy (EJS) following laparoscopic total gastrectomy (LTG) remains technically challenging. To popularize LTG, a secure method of reconstruction must be developed. We present a simple and safe technique for intracorporeal EJS following LTG. METHODS: Our modified technique for intracorporeal EJS as a part of Roux-en-Y reconstruction following LTG incorporates an isoperistaltic stapled EJS with closure of the entry hole using two unidirectional barbed sutures. First, a side-to-side isoperistaltic EJS is created between the dorsal and left side of the esophagus and the jejunal arm. Second, the opening for the stapler is closed with a two-layer continuous suture using two 15-cm 3-0 V-Loc suture devices. The full-thickness inner layer closure commences from the sides of the staple lines and progresses toward the center of the enterotomy. During suturing, the remaining thread is utilized to apply tension and lift the enterotomy. Once the full-thickness layer closure is complete at the center of the enterotomy, suturing of the second seromuscular layer is started in the forward direction toward each corner to give a crossover-shaped suturing line. RESULTS: From February 2012 to October 2017, 27 patients with gastric cancer underwent LTG with intracorporeal stapled EJS as a part of Roux-en-Y reconstruction. All procedures were successfully performed without any intra- or postoperative anastomosis-related complications. No conversion to other procedures was required. The mean suturing time was 19.1 ± 9.5 min. The mean postoperative time to tolerating a liquid diet was 3.3 days, and the mean hospital stay was 12.1 days. CONCLUSIONS: We herein report our procedure for intracorporeal EJS using a linear stapler and barbed sutures. This technique is simple and feasible and has acceptable morbidity.

Protocol for enhanced recovery after surgery improves short-term outcomes for patients with gastric cancer: a randomized clinical trial.

BACKGROUND: The feasibility of the use of the enhanced recovery after surgery (ERAS) protocol in patients with gastric cancer remains unclear. METHODS: This study was a single-center, prospective randomized trial involving patients with gastric cancer undergoing curative gastrectomy. The primary end point was the length of postoperative hospital stay. Secondary end points were the postoperative complication rate, admission costs, weight loss, and amount of physical activity. RESULTS: From July 2013 to June 2015, we randomized 148 patients into an ERAS protocol group (n = 73) and a conventional protocol group (n = 69); six patients withdrew from the study. The hospital stay was significantly shorter in the ERAS protocol group than in the conventional protocol group (9 days vs 10 days; P = 0.037). The ERAS protocol group had a significantly lower rate of postoperative complications of grade III or higher (4.1% vs 15.4%; P = 0.042) and reduced costs of hospitalization (JPY 1,462,766 vs JPY 1,493,930; P = 0.045). The ratio of body weight to preoperative weight at 1 week and 1 month after the operation was higher in the ERAS protocol group (0.962 vs 0.957, P = 0.020, and 0.951 vs 0.937, P = 0.021, respectively). The ERAS protocol group recorded more physical activity in the first week after surgery. CONCLUSIONS: The ERAS protocol is safe and efficient, and seems to improve the postoperative course of patients with gastric cancer.

Roles of common subunits within distinct multisubunit complexes.

Currently, there is no method to distinguish between the roles of a subunit in one multisubunit protein complex from its roles in other complexes in vivo. This is because a mutation in a common subunit will affect all complexes containing that subunit. Here, we describe a unique method to discriminate between the functions of a common subunit in different multisubunit protein complexes. In this method, a common subunit in a multisubunit protein complex is genetically fused to a subunit that is specific to that complex and point mutated. The resulting phenotype(s) identify the specific function(s) of the subunit in that complex only. Histone H2B is a common subunit in nucleosomes containing H2A/H2B or Htz1/H2B dimers. The H2B was fused to H2A or Htz1 and point mutated. This strategy revealed that H2B has common and distinct functions in different nucleosomes. This method could be used to study common subunits in other multisubunit protein complexes.

Preserving Mafa expression in diabetic islet ß-cells improves glycemic control in vivo.

The murine Mafa transcription factor is a key regulator of postnatal islet ß-cell activity, affecting insulin transcription, insulin secretion, and ß-cell mass. Human MAFA expression is also markedly decreased in islet ß-cells of type 2 diabetes mellitus (T2DM) patients. Moreover, levels are profoundly reduced in db/db islet ß-cells, a mouse model of T2DM. To examine the significance of this key islet ß-cell-enriched protein to glycemic control under diabetic conditions, we generated transgenic mice that conditionally and specifically produced Mafa in db/db islet ß-cells. Sustained expression of Mafa resulted in significantly lower plasma glucose levels, higher plasma insulin, and augmented islet ß-cell mass. In addition, there was increased expression of insulin, Slc2a2, and newly identified Mafa-regulated genes involved in reducing ß-cell stress, like Gsta1 and Gckr. Importantly, the levels of human GSTA1 were also compromised in T2DM islets. Collectively, these results illustrate how consequential the reduction in Mafa activity is to islet ß-cell function under pathophysiological conditions.

Laparoscopic gastrointestinal anastomoses using knotless barbed absorbable sutures are safe and reproducible: a single-center experience with 242 patients.

OBJECTIVE: Intracorporeal reconstruction of the digestive tract is technically challenging. The V-Loc 180 wound closure device (Covidien) is a self-anchoring unidirectional barbed suture that obviates the need for knot tying. The aim of this prospective cohort study was to investigate the use of the novel suture in gastrointestinal enterotomy closure. METHODS: The subjects comprised patients with malignant disease who were scheduled to undergo laparoscopic gastrectomy with curative intent. The barbed suture was used to close the entry hole for the linear stapler during intracorporeal reconstruction following laparoscopic gastric resection. The primary endpoint was the proportion of patients who developed anastomotic leakage at the site where the barbed suture was applied. RESULTS: Between July 2012 and March 2015, 242 patients were enrolled. Of 362 anastomoses, the enterotomy hole at 256 sites was closed using the barbed suture. These 256 sites consisted of 95 gastroduodenostomies, 25 gastrogastrostomies, 13 gastrojejunostomies, 90 jejunojejunostomies, 17 esophagojejunostomies and 16 primary closures of the stomach following local gastric resection. There were no anastomosis-related complications, conversion to usual sutures, mechanical closure of the entry hole and reoperation due to adhesive obstructions or mortality over a median follow-up period of 17.8 months. CONCLUSIONS: The use of the unidirectional barbed absorbable suture for gastrointestinal closure is safe and effective in laparoscopic gastrectomy.

Stomach Chitinase from Japanese Sardine Sardinops melanostictus: Purification, Characterization, and Molecular Cloning of Chitinase Isozymes with a Long Linker.

Fish express two different chitinases, acidic fish chitinase-1 (AFCase-1) and acidic fish chitinase-2 (AFCase-2), in the stomach. AFCase-1 and AFCase-2 have different degradation patterns, as fish efficiently degrade chitin ingested as food. For a comparison with the enzymatic properties and the primary structures of chitinase isozymes obtained previously from the stomach of demersal fish, in this study, we purified chitinase isozymes from the stomach of Japanese sardine Sardinops melanostictus, a surface fish that feeds on plankton, characterized the properties of these isozymes, and cloned the cDNAs encoding chitinases. We also predicted 3D structure models using the primary structures of S. melanostictus stomach chitinases. Two chitinase isozymes, SmeChiA (45 kDa) and SmeChiB (56 kDa), were purified from the stomach of S. melanostictus. Moreover, two cDNAs, SmeChi-1 encoding SmeChiA, and SmeChi-2 encoding SmeChiB were cloned. The linker regions of the deduced amino acid sequences of SmeChi-1 and SmeChi-2 (SmeChi-1 and SmeChi-2) are the longest among the fish stomach chitinases. In the cleavage pattern groups toward short substrates and the phylogenetic tree analysis, SmeChi-1 and SmeChi-2 were classified into AFCase-1 and AFCase-2, respectively. SmeChi-1 and SmeChi-2 had catalytic domains that consisted of a TIM-barrel (ß/α)8-fold structure and a deep substrate-binding cleft. This is the first study showing the 3D structure models of fish stomach chitinases.

Global analysis of core histones reveals nucleosomal surfaces required for chromosome bi-orientation.

The attachment of sister kinetochores to microtubules from opposite spindle poles is essential for faithful chromosome segregation. Kinetochore assembly requires centromere-specific nucleosomes containing the histone H3 variant CenH3. However, the functional roles of the canonical histones (H2A, H2B, H3, and H4) in chromosome segregation remain elusive. Using a library of histone point mutants in Saccharomyces cerevisiae, 24 histone residues that conferred sensitivity to the microtubule-depolymerizing drugs thiabendazole (TBZ) and benomyl were identified. Twenty-three of these mutations were clustered at three spatially separated nucleosomal regions designated TBS-I, -II, and -III (TBZ/benomyl-sensitive regions I-III). Elevation of mono-polar attachment induced by prior nocodazole treatment was observed in H2A-I112A (TBS-I), H2A-E57A (TBS-II), and H4-L97A (TBS-III) cells. Severe impairment of the centromere localization of Sgo1, a key modulator of chromosome bi-orientation, occurred in H2A-I112A and H2A-E57A cells. In addition, the pericentromeric localization of Htz1, the histone H2A variant, was impaired in H4-L97A cells. These results suggest that the spatially separated nucleosomal regions, TBS-I and -II, are necessary for Sgo1-mediated chromosome bi-orientation and that TBS-III is required for Htz1 function.

[Game addiction].

The purpose of this article is to analyze the South Korea and China of computer game research, and the current state of research in Japan. Excessive game actions were analyzed by PET-MRI, MRI, fMRI, NIRS, EEG. These results showed that the prefrontal cortical activity decreased during game play. Also, game addiction causes damage to the prefrontal cortex. The NIRS-EEG and simultaneous recording, during game play correspond well with the decrease of ß band and oxygen-hemoglobin. The α band did not change with game play. However, oxygen-hemoglobin decreased during game play. South Korea, game addiction measures have been analyzed since 2002, but in Japan the research is recent.

A novel function of Onecut1 protein as a negative regulator of MafA gene expression.

The transcription factor MafA is a key regulator of insulin gene expression and maturation of islet ß cells. Despite its importance, the regulatory mechanism of MafA gene expression is still unclear. To identify the transcriptional regulators of MafA, we examined various transcription factors, which are potentially involved in ß cell differentiation. An adenovirus-mediated overexpression study clearly demonstrated that Onecut1 suppresses the promoter activity of MafA through the Foxa2-binding cis-element on the MafA enhancer region (named area A). However, ChIP analysis showed that Foxa2 but not Onecut1 could directly bind to area A. Furthermore, overexpression of Onecut1 inhibited the binding of Foxa2 onto area A upon ChIP analysis. Importantly, insertion of a mutation in the Foxa2-binding site of area A significantly decreased the promoter activity of MafA. These findings suggest that Onecut1 suppresses MafA gene expression through the Foxa2-binding site. In the mouse pancreas, MafA expression was first detected at the latest stage of ß cell differentiation and was scarcely observed in Onecut1-positive cells during pancreas development. In addition, Onecut1 expression was significantly increased in the islets of diabetic db/db mice, whereas MafA expression was markedly decreased. The improved glucose levels of db/db mice with insulin injections significantly reduced Onecut1 expression and rescued the reduction of MafA expression. These in vivo experiments also suggest that Onecut1 is a negative regulator of MafA gene expression. This study implicates the novel role of Onecut1 in the control of normal ß cell differentiation and its involvement in ß cell dysfunction under diabetic conditions by suppressing MafA gene expression.

Association of scan frequency with CGM-derived metrics and influential factors in adults with type 1 diabetes mellitus.

Introduction: This study aimed to investigate the association between scan frequency and intermittently scanned continuous glucose monitoring (isCGM) metrics and to clarify the factors affecting scan frequency in adults with type 1 diabetes mellitus (T1D). Methods: We enrolled adults with T1D who used FreeStyle® Libre. Scan and self-monitoring of blood glucose (SMBG) frequency and CGM metrics from the past 90-day glucose data were collected. The receiver operating characteristic curve was plotted to obtain the optimal cutoff values of scan frequency for the target values of time in range (TIR), time above range (TAR), and time below range (TBR). Results: The study was conducted on 211 adults with T1D (mean age, 50.9 ± 15.2 years; male, 40.8%; diabetes duration, 16.4 ± 11.9 years; duration of CGM use, 2.1 ± 1.0 years; and mean HbA1c, 7.6 ± 0.9%). The average scan frequency was 10.5 ± 3.3 scan/day. Scan frequency was positively correlated with TIR and negatively correlated with TAR, although it was not significantly correlated with TBR. Scan frequency was positively correlated with the hypoglycemia fear survey-behavior score, while it was negatively correlated with some glycemic variability metrics. Adult patients with T1D and good exercise habits had a higher scan frequency than those without exercise habits. The AUC for > 70% of the TIR was 0.653, with an optimal cutoff of 11 scan/day. Conclusions: In real-world conditions, frequent scans were linked to improved CGM metrics, including increased TIR, reduced TAR, and some glycemic variability metrics. Exercise habits and hypoglycemia fear-related behavior might affect scan frequency. Our findings could help healthcare professionals use isCGM to support adults with T1D.Clinical Trial Registry No. UMIN000039376.

Nucleosome surface containing nucleosomal DNA entry/exit site regulates H3-K36me3 via association with RNA polymerase II and Set2.

A nucleosome is composed of intrinsically disordered histone tails and a structured nucleosome core surrounded by DNA. A variety of modifiable residues on the intrinsically disordered histone tails have been identified in the last decade. Mapping of the functional residues on the structured nucleosome core surface was recently initiated by global analysis of a comprehensive histone point mutant library (histone-GLibrary). It stands to reason that a functional relationship exists between modifiable residues on the intrinsically disordered histone tails and functional residues on the structured nucleosome core; however, this matter has been poorly explored. During transcription elongation, trimethylation of histone H3 at lysine 36 (H3-K36me3) is mediated by histone methyltransferase Set2, which binds to RNA polymerase II. Here, we used a histone-GLibrary that encompasses the nucleosomal DNA entry/exit site to show that six residues (H2A-G107, H2A-I112, H2A-L117, H3-T45, H3-R49 and H3-R52) form a surface on the structured nucleosome core and regulate H3-K36me3. Trimethylation at H3-K4 introduced by histone methyltransferase Set1 was not affected by the mutation of any of the six residues. Chromatin immunoprecipitation analysis showed that most of these residues are critical for the chromatin association of RNA polymerase II and Set2, suggesting that these components regulate H3-K36me3 through functional interactions with the structured nucleosome core surface.

Cell-SELEX based selection and characterization of DNA aptamer recognizing human hepatocarcinoma.

Single-stranded DNA aptamers recognizing human hepatocarcinoma were isolated by means of a systematic evolution of ligands by exponential enrichment using whole cells as targets (cell-SELEX). After 11 rounds of cell-SELEX procedure using human hepatoma HepG2 cells as targets and human normal hepatocyte cells as counterparts, 12 independent DNA aptamer candidate sequences were obtained. The specific interaction between selected DNA aptamers and targeted cell was confirmed. Dissociation constants of the 12 sequences obtained were also estimated in the range of 19-450nM. Moreover, the consensus secondary structure was found in the isolated aptamers, which was responsible to the recognition of HepG2 cells.

To Use or Not to Use a Self-monitoring of Blood Glucose System? Real-world Flash Glucose Monitoring Patterns Using a Cluster Analysis of the FGM-Japan Study.

Objective This study investigated self-monitoring of blood glucose (SMBG) adherence and flash glucose monitoring patterns using a cluster analysis in Japanese type 1 diabetes (T1D) patients with intermittently scanned continuous glucose monitoring (isCGM). Methods We measured SMBG adherence and performed a data-driven cluster analysis using a hierarchical clustering in T1D patients from Japan using the FreeStyle Libre system. Clusters were based on three variables (testing glucose frequency and referred Libre data for hyperglycemia or hypoglycemia). Patients We enrolled 209 participants. Inclusion criteria were patients with T1D, duration of isCGM use ≥3 months, age ≥20 years old, and regular attendance at the collaborating center. Results The rate of good adherence to SMBG recommended by a doctor was 85.0%. We identified three clusters: cluster 1 (low SMBG test frequency but high reference to Libre data, 17.7%), cluster 2 (high SMBG test frequency but low reference to Libre data, 34.0%), and cluster 3 (high SMBG test frequency and high reference to Libra data, 48.3%). Compared with other clusters, individuals in cluster 1 were younger, those in cluster 2 had a shorter Libre duration, and individuals in cluster 3 had lower time-in-range, higher severe diabetic distress, and high intake of snacks and sweetened beverages. There were no marked differences in the incidence of diabetic complications and rate of wearing the Libre sensor among the clusters. Conclusion We stratified the patients into three subgroups with varied clinical characteristics and CGM metrics. This new substratification might help tailor diabetes management of patients with T1D using isCGM.

Factors associated with hemoglobin glycation index in adults with type 1 diabetes mellitus: The FGM-Japan study.

AIMS/INTRODUCTION: The discrepancy between HbA1c and glucose exposure may have significant clinical implications; however, the association between the hemoglobin glycation index (HGI) and clinical parameters in type 1 diabetes remains controversial. This study aimed to find the factors associated with HGI (laboratory HbA1c - predicted HbA1c derived from the continuous glucose monitoring [CGM]). MATERIALS AND METHODS: We conducted a cross-sectional study of adults with type 1 diabetes (n = 211, age 50.9 ± 15.2 years old, female sex = 59.2%, duration of CGM use = 2.1 ± 1.0 years). All subjects wore the CGM for 90 days before HbA1c measurement. Data derived from the FreeStyle Libre sensor were used to calculate the glucose management indicator (GMI) and glycemic variability (GV) parameters. HGI was defined as the difference between the GMI and the laboratory HbA1c levels. The participants were divided into three groups according to the HGI tertile (low, moderate, and high). Multivariate regression analyses were performed. RESULTS: The female sex ratio, HbA1c, and % coefficient of variation (%CV) significantly increased over the HGI tertile, while eGFR and Hb decreased over the HGI tertile. In multivariate analysis, the factors associated with HGI were %CV and eGFR, after adjusting for HbA1c level and sex (R2  = 0.44). CONCLUSIONS: This study demonstrated that HGI is associated with female sex, eGFR, and some glycemic variability indices, independently of HbA1c. Minimizing glycemic fluctuations might reduce HGI. This information provides diabetic health professionals and patients with personalized diabetes management for adults with type 1 diabetes.