A phase 1/1b, open-label, dose-escalation study of PD-1 inhibitor, cetrelimab alone and in combination with FGFR inhibitor, erdafitinib in Japanese patients with advanced solid tumors.

Immune checkpoint inhibitors are the leading approaches in tumor immunotherapy. The aim of the study was to establish recommended phase 2 doses (RP2Ds) of intravenous cetrelimab, a checkpoint inhibitor, alone and with oral erdafitinib in Japanese patients with advanced solid tumors. This open-label, non-randomized, dose-escalation phase 1/1b study enrolled adults with advanced solid tumors who were ineligible for standard therapy. Study was conducted in two parts: phase 1a assessed cetrelimab at three dosing levels (80 mg every 2 weeks [Q2W], 240 mg Q2W, and 480 mg Q4W); phase 1b assessed cetrelimab+erdafitinib at two dosing levels (240 mg Q2W + 6 mg once daily [QD] and 240 mg Q2W + 8 mg QD). Primary endpoint was frequency and severity of dose-limiting toxicities (DLTs) of cetrelimab ± erdafitinib. In total 22 patients (phase 1a, n = 9; phase 1b, n = 13) were enrolled. Median duration of follow-up was 8.64 months in phase 1a and 2.33 months in phase 1b. In phase 1a, DLTs weren't reported while in phase 1b, 1 patient who received 240 mg cetrelimab + 6 mg erdafitinib reported Stevens-Johnson syndrome (grade 3, immune-related). Overall, 88.9% patients in phase 1a (grade ≥ 3: 44.4%) and 100.0% in phase 1b (grade ≥ 3: 53.8%) experienced ≥ 1 treatment-related adverse events (TEAEs); 33.3% in phase 1a and 38.5% in phase 1b reported serious TEAEs, of which 11.1% patients in phase 1a and 15.4% in phase 1b had TEAEs which led to treatment discontinuation. Cetrelimab alone and in combination with erdafitinib showed manageable safety in Japanese patients with advanced solid tumors. RP2Ds were determined as 480 mg cetrelimab Q4W for monotherapy, and cetrelimab 240 mg Q2W + erdafitinib 8 mg QD for combination therapy.

Antenatal Therapy for Fetal Supraventricular Tachyarrhythmias: Multicenter Trial.

BACKGROUND: Standardized treatment of fetal tachyarrhythmia has not been established. OBJECTIVES: This study sought to evaluate the safety and efficacy of protocol-defined transplacental treatment for fetal supraventricular tachycardia (SVT) and atrial flutter (AFL). METHODS: In this multicenter, single-arm trial, protocol-defined transplacental treatment using digoxin, sotalol, and flecainide was performed for singleton pregnancies from 22 to <37 weeks of gestation with sustained fetal SVT or AFL ≥180 beats/min. The primary endpoint was resolution of fetal tachyarrhythmia. Secondary endpoints were fetal death, pre-term birth, and neonatal arrhythmia. Adverse events (AEs) were also assessed. RESULTS: A total of 50 patients were enrolled at 15 institutions in Japan from 2010 to 2017; short ventriculoatrial (VA) SVT (n = 17), long VA SVT (n = 4), and AFL (n = 29). One patient with AFL was excluded because of withdrawal of consent. Fetal tachyarrhythmia resolved in 89.8% (44 of 49) of cases overall and in 75.0% (3 of 4) of cases of fetal hydrops. Pre-term births occurred in 20.4% (10 of 49) of patients. Maternal AEs were observed in 78.0% (39 of 50) of patients. Serious AEs occurred in 1 mother and 4 fetuses, thus resulting in discontinuation of protocol treatment in 4 patients. Two fetal deaths occurred, mainly caused by heart failure. Neonatal tachyarrhythmia was observed in 31.9% (15 of 47) of neonates within 2 weeks after birth. CONCLUSIONS: Protocol-defined transplacental treatment for fetal SVT and AFL was effective and tolerable in 90% of patients. However, it should be kept in mind that serious AEs may take place in fetuses and that tachyarrhythmias may recur within the first 2 weeks after birth.

Core factors promoting a continuum of care for maternal, newborn, and child health in Japan.

Providing a continuum of care (CoC) is important strategy for improving maternal, newborn, and child health (MNCH). Japan's current very low maternal and infant mortality rates suggest that its CoC for MNCH is good. In this paper, we attempt to clarify how CoC and low mortality rates are being maintained in Japan, by examining the entire MNCH service provision system. First, we examine two important tools for integrated service provision, the Maternal and Child Health (MCH) Handbook and registration of pregnant women with local governments, both introduced in 1942. Second, we explore the incentives provided by the MNCH system that prompt actors to participate in it. The three actors identified are service users (e.g., mothers and babies), medical professionals, and local governments. Through system design, all three actors benefit in ways that incentivize them to use MNCH services, which consequently connects service users with resources: all service users regardless of financial status, nationality, and location can receive free MNCH services such as antenatal care, assistance with childbirth, postnatal care, and immunizations; using the handbook, service users obtain health information, and medical professionals obtain the health records of pregnant women and their children as well as access examination fees from the local government by submitting vouchers in the handbook; local governments can then identify pregnant women for follow-up and provide health information and administrative services. As a result, the coverage rate of the MCH Handbook has reached 100% and MNCH services coverage could potentially reach the same level.

The impact of intrauterine treatment on fetal tachycardia: a nationwide survey in Japan.

OBJECTIVES: To investigate the clinical course of fetal tachycardia and analyze the impact of intrauterine treatment on the postnatal treatment and patient outcomes. STUDY DESIGN: This was a retrospective review of cases of fetal tachycardia that occurred from 2004 to 2006. Data were collected from questionnaires that were sent to all 750 secondary or tertiary perinatal care centers in Japan. RESULTS: Eighty-two cases (14 with fetal hydrops) were analyzed (supraventricular tachycardia [SVT], n = 52; atrial flutter [AFL], n = 23; and ventricular tachycardia, n = 7). The overall mortality was 3.7%. Intrauterine treatment was performed for 41 fetuses (50.0%). Digoxin, flecainide and sotalol were mainly used for SVT and AFL. Fetal tachycardia resolved in 90.0% (27/30) of the cases without fetal hydrops and 90.9% (10/11) of the cases with fetal hydrops. Intrauterine treatment significantly reduced the incidence of cesarean delivery (29.3 vs. 70.7%, p < .01), preterm birth (12.2 vs. 41.5%, p = .02) and neonatal arrhythmias (48.8 vs. 78.0%, p = .01) in comparison to untreated fetuses. CONCLUSIONS: This nationwide survey revealed that intrauterine treatment was performed for approximately half of the cases of fetal tachycardia and was associated with lower rates of cesarean delivery, premature birth and neonatal arrhythmias in comparison to untreated fetuses.

Antenatal antiarrhythmic treatment for fetal tachyarrhythmias: a study protocol for a prospective multicentre trial.

INTRODUCTION: Several retrospective or single-centre studies demonstrated the efficacy of transplacental treatment of fetal tachyarrhythmias. Our retrospective nationwide survey showed that the fetal therapy will be successful at an overall rate of 90%. For fetuses with hydrops, the treatment success rate will be 80%. However, standard protocol has not been established. The objective of this study is to evaluate the efficacy and safety of the protocol-defined transplacental treatment of fetal tachyarrhythmias. Participant recruitment began in October 2010. METHODS AND ANALYSIS: The current study is a multicentre, single-arm interventional study. A total of 50 fetuses will be enrolled from 15 Japanese institutions. The protocol-defined transplacental treatment is performed for singletons with sustained fetal tachyarrhythmia ≥180 bpm, with a diagnosis of supraventricular tachycardia or atrial flutter. Digoxin, sotalol, flecainide or a combination is used for transplacental treatment. The primary endpoint is disappearance of fetal tachyarrhythmias. The secondary endpoints are fetal death related to tachyarrhythmia, proportion of preterm birth, rate of caesarean section attributable to fetal arrhythmia, improvement in fetal hydrops, neonatal arrhythmia, neonatal central nervous system disorders and neonatal survival. Maternal, fetal and neonatal adverse events are evaluated at 1 month after birth. Growth and development are also evaluated at 18 and 36 months of corrected age. ETHICS AND DISSEMINATION: The Institutional Review Board of the National Cerebral and Cardiovascular Center of Japan has approved this study. Our findings will be widely disseminated through conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: UMIN Clinical Trials Registry UMIN000004270.

Evaluating the impact of continuous quality improvement methods at hospitals in Tanzania: a cluster-randomized trial.

OBJECTIVE: To evaluate the impact of implementing continuous quality improvement (CQI) methods on patient's experiences and satisfaction in Tanzania. DESIGN: Cluster-randomized trial, which randomly allocated district-level hospitals into treatment group and control group, was conducted. SETTING: Sixteen district-level hospitals in Kilimanjaro and Manyara regions of Tanzania. PARTICIPANTS: Outpatient exit surveys targeting totally 3292 individuals, 1688 in the treatment and 1604 in the control group, from 3 time-points between September 2011 and September 2012. INTERVENTION: Implementation of the 5S (Sort, Set, Shine, Standardize, Sustain) approach as a CQI method at outpatient departments over 12 months. MAIN OUTCOME MEASURES: Cleanliness, waiting time, patient's experience, patient's satisfaction. RESULTS: The 5S increased cleanliness in the outpatient department, patients' subjective waiting time and overall satisfaction. However, negligible effects were confirmed for patient's experiences on hospital staff behaviours. CONCLUSIONS: The 5S as a CQI method is effective in enhancing hospital environment and service delivery; that are subjectively assessed by outpatients even during the short intervention period. Nevertheless, continuous efforts will be needed to connect CQI practices with the further improvement in the delivery of quality health care.

Fetal bradyarrhythmia associated with congenital heart defects - nationwide survey in Japan.

BACKGROUND: Because there is limited information on fetal bradyarrhythmia associated with congenital heart defects (CHD), we investigated its prognosis and risk factors. METHODS AND RESULTS: In our previous nationwide survey of fetal bradyarrhythmia from 2002 to 2008, 38 fetuses had associated CHD. Detailed clinical data were collected from secondary questionnaires on 29 fetuses from 18 institutions, and were analyzed. The 29 fetuses included 22 with isomerism, 4 with corrected transposition of the great arteries (TGA) and 3 with critical pulmonary stenosis; 14 had complete atrioventricular block (AVB), 8 had second-degree AVB, and 16 had sick sinus syndrome; 5 died before birth, and 10 died after birth (5 in the neonatal period). Neonatal and overall survival rates for fetal bradyarrhythmia with CHD were 66% and 48%, respectively. Pacemaker implantation was needed in 17 cases (89%). Beta-sympathomimetics were administered in utero in 13 cases and were effective in 6, but were not associated with prognosis. All cases of corrected TGA or ventricular rate ≥70 beats/min survived. A ventricular rate <55 beats/min had significant effects on fetal myocardial dysfunction (P=0.02) and fetal hydrops (P=0.04), resulting in high mortality. CONCLUSIONS: The prognosis of fetal bradyarrhythmia with CHD is still poor. The type of CHD, fetal myocardial dysfunction, and fetal hydrops were associated with a poor prognosis, depending on the ventricular rate.

Is the Maternal and Child Health (MCH) handbook effective in improving health-related behavior? Evidence from Palestine.

OBJECTIVE: This study examines the effect of the Maternal and Child Health (MCH) handbook--a home-based health record--on women's knowledge and behavior in the Jericho and Ramallah Governorates of Palestine. METHODS: This study uses a repeated, cross-sectional data set in which pre- and post-intervention situations are incorporated on two groups: those exposed and those not exposed to the MCH handbook. We employed a difference-in-difference regression analysis utilizing a pre-tested knowledge, attitude, and practice survey of women at 24 MCH 'treatment' centers (N=260, 270, pre-/post-) in comparison with the women at 6 MCH centers (N=70, 70, pre-/post-) where the MCH handbook was not released. A trained facilitator conducted a series of focus group discussions with 42 women who were the clients of MCH services and 25 health providers, both from the intervention area, to confirm the results obtained from the quantitative study. FINDINGS: Knowledge related to MCH such as the importance of exclusive breastfeeding and how to cope with the risks of rupture of membranes during pregnancy increased among MCH handbook users, especially among less-educated women. The MCH handbook may be an effective tool for communication with health providers and husbands, for both highly educated and less-educated women during their first pregnancy. Our results suggest that although less-educated women rarely read the handbook themselves at home, they became familiar with health information and options related to MCH through personalized guidance that was provided by health providers at health facilities utilizing MCH handbook. CONCLUSION: The MCH handbook may be an effective tool to improve (i) communication between the client and the health provider and (ii) women's knowledge- and health-seeking behaviors related to maternal, newborn, and child health.

Post treatment with an FGF chimeric growth factor enhances epithelial cell proliferation to improve recovery from radiation-induced intestinal damage.

PURPOSE: A fibroblast growth factor (FGF) 1-FGF2 chimera (FGFC) was created previously and showed greater structural stability than FGF1. This chimera was capable of stimulating epithelial cell proliferation much more strongly than FGF1 or FGF2 even without heparin. Therefore FGFC was expected to have greater biologic activity in vivo. This study evaluated and compared the protective activity of FGFC and FGF1 against radiation-induced intestinal injuries. METHODS AND MATERIALS: We administered FGFC and FGF1 intraperitoneally to BALB/c mice 24 h before or after total-body irradiation (TBI). The numbers of surviving crypts were determined 3.5 days after TBI with gamma rays at doses ranging from 8 to 12 Gy. RESULTS: The effect of FGFC was equal to or slightly superior to FGF1 with heparin. However, FGFC was significantly more effective in promoting crypt survival than FGF1 (p < 0.01) when 10 µg of each FGF was administered without heparin before irradiation. In addition, FGFC was significantly more effective at promoting crypt survival (p < 0.05) than FGF1 even when administered without heparin at 24 h after TBI at 10, 11, or 12 Gy. We found that FGFC post treatment significantly promoted 5-bromo-2'-deoxyuridine incorporation into crypts and increased crypt depth, resulting in more epithelial differentiation. However, the number of apoptotic cells in FGFC-treated mice decreased to almost the same level as that in FGF1-treated mice. CONCLUSIONS: These findings suggest that FGFC strongly enhanced radioprotection with the induction of epithelial proliferation without exogenous heparin after irradiation and is useful in clinical applications for both the prevention and post treatment of radiation injuries.

Morphological and histochemical study of the nasal cavity and fused olfactory bulb of the brown-eared bulbul, Hysipetes amaurotis.

The brown-eared bulbul (Hysipetes amaurotis) is commonly found in Japan where it is regarded as a harmful bird that causes damage to agricultural products. Few studies have investigated the sensory apparatus of this bird, and consequently little is known of the sensory modalities it uses. Here we analyzed the anatomical and histological properties of the nasal cavity and olfactory bulb (OB) of the bulbul in order to investigate the functional level of olfaction in this species. Although both anterior and maxillary conchae were observed in the bulbul nasal cavity, there was no structure equivalent to the posterior concha. The OB located on the ventral side of the anterior extremity of the cerebrum and the ratio of olfactory bulb size to that of the cerebral hemisphere were very small. Interestingly, the left and right OBs were completely fused at the midline of the cerebrum. Furthermore, certain types of lectins that bind to the olfactory nerve of vertebrates with a well-developed sense of smell also bound positively to the olfactory nerve and glomerular layers of the bulbul OB. These findings suggest that the brown-eared bulbul has an anatomically and functionally less well developed sense of smell compared to other avian species. Although the molecular and developmental mechanisms underlying the fusion of the OB remain unknown, we suggest that the fused OB may offer a unique model for studying the evolution and development of the central olfactory nervous system in vertebrates.

Histological properties of the nasal cavity and olfactory bulb of the Japanese jungle crow Corvus macrorhynchos.

The nasal cavity and olfactory bulb (OB) of the Japanese jungle crow (Corvus macrorhynchos) were studied using computed tomography (CT) and histochemical staining. The nasal septum divided the nasal cavity in half. The anterior and maxillary conchae were present on both sides of the nasal cavity, but the posterior concha was indistinct. A small OB was present on the ventral surface of the periphery of the cerebrum. The OB-brain ratio--the ratio of the size of the OB to that of the cerebral hemisphere--was 6.13. The olfactory nerve bundles projected independently to the OB, which appeared fused on gross examination. Histochemical analysis confirmed the fusion of all OB layers. Using a neural tracer, we found that the olfactory nerve bundles independently projected to the olfactory nerve layer (ONL) and glomerular layer (GL) of the left and right halves of the fused OB. Only 4 of 21 lectins bound to the ONL and GL. Thus, compared with mammals and other birds, the jungle crow may have a poorly developed olfactory system and an inferior sense of olfaction. However, it has been contended recently that the olfactory abilities of birds cannot be judged from anatomical findings alone. Our results indicate that the olfactory system of the jungle crow is an interesting research model to evaluate the development and functions of vertebrate olfactory systems.

Comparison of expression profiles of several fibroblast growth factor receptors in the mouse jejunum: suggestive evidence for a differential radioprotective effect among major FGF family members and the potency of FGF1.

Several members of the fibroblast growth factor (FGF) family have the potential to protect the intestine against the side effects of radiation therapy. FGF1 is capable of signaling through all subtypes of FGF receptors (FGFRs), whereas FGF7 and FGF10 activate only the epithelial-specific subtype, FGFR2IIIb (FGFR2b). The present study compared the protective activity of FGF1, FGF7 and FGF10 and examined the profiles of FGFR expression in the jejunum of BALB/c mice given total-body irradiation (TBI) with gamma rays. TBI caused drastic increases in FGFR1-4 transcript levels in the jejunum. However, FGFR2b protein temporarily decreased at 12 and 24 h after irradiation. FGF1 pretreatment minimized the number of apoptotic cells in jejunal crypts at 16 and 24 h after irradiation and increased crypt survival most effectively. In addition, pretreatment with FGF7 or FGF10 decreased FGFR1 transcript levels. The greater effectiveness of FGF1 to enhance crypt survival was also observed even when each FGF was administered 1 h after irradiation. These findings indicate that FGF1 is more potent than FGF7 or FGF10 for protection of the intestine against radiation exposure and suggest that the profiles of FGFR expression in the intestine favor the FGF1 signaling pathway before and during the initial period after irradiation.

Evaluation of radiation-induced hair follicle apoptosis in mice and the preventive effects of fibroblast growth factor-1.

Radiation-induced hair loss is a clinically important, but under-researched topic. The aim of the study was to develop an in vivo assay system for radiation-induced apoptosis in hair follicles to promote hair research and exploit new radioprotectors. BALB/c mice received total body irradiation (TBI) with gamma-rays at doses in the range from 8 to 16 Gy at 6 days after depilation. Pathological changes were detected progressively in the hair follicles over the time course after TBI and the dystrophy was evaluated on the basis of stage-specific parameters reported previously, which were found to be well-suited for classification of the radiation-induced hair follicle dystrophy. As a result, regression from anagen to catagen was determined in these follicles after irradiation. In addition, radiation-induced apoptosis was a good early dystrophic parameter. In this system, it was found that fibroblast growth factor-1 effectively prevented hair follicle apoptosis in mice.

Correlation between body weight (epididymal fat) and permeation rate of serum leptin through the blood-brain barrier (BBB) in male rats aged 8 months.

In this study, in order to clarify the kinetics of leptin, we focused on the ratio of leptin concentrations in cerebrospinal fluid and serum in aged male rats, and examined the weight of epididymal fat, and the passage rate of leptin through the blood-brain barrier. In the lighter animals, the epididymal fat weight was low, while leptin concentrations in the serum and cerebrospinal fluid were also low. Conversely, in the heavier animals, the weight of epididymal fat and leptin concentrations in the serum and cerebrospinal fluid were higher. With regard to the ratio of leptin in the cerebrospinal fluid and serum, the passage rate of leptin through the blood-brain barrier was lower in the heavier animals than in the lighter animals.

An FGF1:FGF2 chimeric growth factor exhibits universal FGF receptor specificity, enhanced stability and augmented activity useful for epithelial proliferation and radioprotection.

Structural instability of wild-type fibroblast growth factor (FGF)-1 and its dependence on exogenous heparin for optimal activity diminishes its potential utility as a therapeutic agent. Here we evaluated FGFC, an FGF1:FGF2 chimeric protein, for its receptor affinity, absolute heparin-dependence, stability and potential clinical applicability. Using BaF3 transfectants overexpressing each FGF receptor (FGFR) subtype, we found that, like FGF1, FGFC activates all of the FGFR subtypes (i.e., FGFR1c, FGFR1b, FGFR2c, FGFR2b, FGFR3c, FGFR3b and FGFR4) in the presence of heparin. Moreover, FGFC activates FGFRs even in the absence of heparin. FGFC stimulated keratinocytes proliferation much more strongly than FGF2, as would be expected from its ability to activate FGFR2b. FGFC showed greater structural stability, biological activity and resistance to trypsinization, and less loss in solution than FGF1 or FGF2. When FGFC was intraperitoneally administered to BALB/c mice prior to whole body gamma-irradiation, survival of small intestine crypts was significantly enhanced, as compared to control mice. These results suggest that FGFC could be useful in a variety of clinical applications, including promotion of wound healing and protection against radiation-induced damage.

Validity and reliability of the Physical Activity Scale for the Elderly (PASE) in Japanese elderly people.

AIM: In Japan, there are no valid and reliable physical activity questionnaires for elderly people. In this study, we translated the Physical Activity Scale for the Elderly (PASE) into Japanese and assessed its validity and reliability. METHODS: Three hundred and twenty-five healthy and elderly subjects over 65 years were enrolled. Concurrent validity was evaluated by Spearman's rank correlation coefficient between PASE scores and an accelerometer (waking steps and energy expenditure), a physical activity questionnaire for adults in general (the Japan Arteriosclerosis Longitudinal Study Physical Activity Questionnaire, JALSPAQ), grip strength, mid-thigh muscle area per bodyweight, static valance and bodyfat percentage. Reliability was evaluated by the test-retest method over a period of 3-4 weeks. RESULTS: The mean PASE score in this study was 114.9. The PASE score was significantly correlated with walking steps (rho = 0.17, P = 0.014), energy expenditure (rho = 0.16, P = 0.024), activity measured with the JALSPAQ (rho = 0.48, P < 0.001), mid-thigh muscle area per bodyweight (rho = 0.15, P = 0.006) and static balance (rho = 0.19, P = 0.001). The proportion of consistency in the response between the first and second surveys was adequately high. The intraclass correlation coefficient for the PASE score was 0.65. CONCLUSIONS: The Japanese version of PASE was shown to have acceptable validity and reliability. The PASE is useful to measure the physical activity of elderly people in Japan.

Involvement of intracellular expression of FGF12 in radiation-induced apoptosis in mast cells.

Several fibroblast growth factors (FGFs) are able to reduce and improve radiation-induced tissue damage through the activation of surface fibroblast growth factor receptors (FGFRs). In contrast, some FGFs lack classical signal sequences, which play roles in the release of FGFs, and the intracellular function of these FGFs is not well clarified. In this study, we evaluated the transcript levels of 22 FGFs in a human mast cell line, HMC-1, using quantitative RT-PCR and found that FGF2 and FGF12 were expressed in HMC-1 cells. FGF12 not only lacks classical signal sequences but also fails to activate FGFRs. HMC-1 cells were transfected with an expression vector of FGF12 to clarify the intracellular function of FGF12 after irradiation. The overexpression of FGF12 in HMC-1 cells decreased ionizing radiation-induced apoptosis, and siRNA-mediated repression of FGF12 expression augmented apoptosis in HMC-1 cells. The overexpression of FGF12 strongly suppressed the marked augmentation of apoptosis induced by inhibition of the MEK/ERK pathway with PD98059. In contrast, the mitogen-activated protein kinase (MAPK) scaffold protein islet brain 2 (IB2), which was reported to bind to FGF12, did not interfere with the anti-apoptotic effect of FGF12. The expression of FGF12 transcripts was also detected in murine cultured mast cells derived from bone marrow or fetal skin. These findings suggest that FGF12 intracellularly suppresses radiation-induced apoptosis in mast cells independently of IB2.

Hydrogen peroxide as a potential mediator of the transcriptional regulation of heparan sulphate biosynthesis in keratinocytes.

Ionizing radiation is one of the types of oxidative stress that has a number of damaging effects on cutaneous tissues. One of the histological features of radiation-induced cutaneous fibrosis is the accumulation of extracellular matrix (ECM) components, including heparan sulfate proteoglycan (HSPG), which are required for the repair of tissue damage, and operate by interacting with a variety of growth factors. In this study, we established a model of human HaCaT keratinocytes overexpressing anti-oxidative enzyme genes to elucidate the mechanism of oxidative stress leading to the accumulation of HSPG and the role of its accumulation. Catalase overexpression induced an increase in anti-HS antibody (10E4) epitope expression in these cells. Western blotting showed that the smeared bands of HSPG were obviously shifted to a higher molecular weight in the catalase transfectants due to glycosylation. After heparitinase I treatment, the core proteins of HSPG were expressed in the catalase transfectants to almost the same extent as in the control cells. In addition, the transcript levels of all the enzymes required for the synthesis of the heparan sulfate chain were estimated in the catalase transfectant clones. The levels of five enzyme transcripts - xylosyltransferase-II (XT-II), EXTL2, D-glucuronyl C5-epimerase (GLCE), HS2-O-sulfotransferase (HS2ST), and HS6-O-sulfotransferase (HS6ST) - were significantly increased in the transfectants. Moreover, hydrogen peroxide was found to down-regulate the levels of these enzymes. By contrast, siRNA-mediated repression of catalase decreased 10E4 epitope expression, the transcript level of HS2ST1, and the growth rate of HaCaT cells. These findings suggested that peroxide-mediated transcriptional regulation of HS metabolism-related genes modified the HS chains in the HaCaT keratinocytes.