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Tomohiro Nakayama

Publications and source records attributed to Tomohiro Nakayama.

At least 19 recordsLinked to original sources
PubMed2025

Clinical and molecular landscape of metastatic extramammary Paget's disease.

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare malignancy without established systemic therapy. EMPD shares molecular features with breast cancer, such as human epidermal growth factor receptor 2 (HER2) and hormone receptor (HR) expression, but their clinical relevance remains unclear. MATERIALS AND METHODS: Tumors from 20 metastatic invasive EMPD cases were analyzed for molecular and biological features. Genomic features, transcriptomic profiles, and HER2 and HR expression status were investigated using immunohistochemistry, fluorescence in situ hybridization, and targeted-genome next-generation sequencing and nCounter BC360 panels. Metastatic breast cancer samples were used as a comparison to clarify metastatic EMPD's clinical relevance. RESULTS: Estrogen receptor expression was observed in 45% of EMPD tumors, while only 10% expressed progesterone receptor. HER2 was overexpressed in 30% of cases, and HER2-directed therapies were durably effective. Among 8 patients with NGS data, 63% (5/8) harbored oncogenic ERBB2 alterations independent of HER2 expression. BC360 profiling revealed biological differences between EMPD and breast cancer, particularly poor biological compatibility for HR-positive tumors. Immune profiling showed that a subset of EMPD tumors exhibited CD8+ T-cell signatures and PD-1/PD-L1 gene expression comparable to triple-negative breast cancer. The median overall survival was 22.1 months (95% CI, 12.0-42.2), with 16 patients (80%) treated with systemic therapy, including anti-HER2 therapy, hormonal therapy, or cytotoxic therapies based on their molecular features. CONCLUSIONS: This study highlights the unique molecular and biological features of metastatic EMPD, emphasizing the need for tailored treatment approaches. This information should be used to guide future clinical strategies for metastatic EMPD.

Humans↗
PubMed2004

The regulatory domain of the inositol 1,4,5-trisphosphate receptor is necessary to keep the channel domain closed: possible physiological significance of specific cleavage by caspase 3.

The type 1 inositol 1,4,5-trisphosphate receptor (IP(3)R1) is an intracellular Ca(2+) channel protein that plays crucial roles in generating complex Ca(2+) signalling patterns. IP(3)R1 consists of three domains: a ligand-binding domain, a regulatory domain and a channel domain. In order to investigate the function of these domains in its gating machinery and the physiological significance of specific cleavage by caspase 3 that is observed in cells undergoing apoptosis, we utilized various IP(3)R1 constructs tagged with green fluorescent protein (GFP). Expression of GFP-tagged full-length IP(3)R1 or IP(3)R1 lacking the ligand-binding domain in HeLa and COS-7 cells had little effect on cells' responsiveness to an IP(3)-generating agonist ATP and Ca(2+) leak induced by thapsigargin. On the other hand, in cells expressing the caspase-3-cleaved form (GFP-IP(3)R1-casp) or the channel domain alone (GFP-IP(3)R1-ES), both ATP and thapsigargin failed to induce increase of cytosolic Ca(2+) concentration. Interestingly, store-operated (-like) Ca(2+) entry was normally observed in these cells, irrespective of thapsigargin pre-treatment. These findings indicate that the Ca(2+) stores of cells expressing GFP-IP(3)R1-casp or GFP-IP(3)R1-ES are nearly empty in the resting state and that these proteins continuously leak Ca(2+). We therefore propose that the channel domain of IP(3)R1 tends to remain open and that the large regulatory domain of IP(3)R1 is necessary to keep the channel domain closed. Thus cleavage of IP(3)R1 by caspase 3 may contribute to the increased cytosolic Ca(2+) concentration often observed in cells undergoing apoptosis. Finally, GFP-IP(3)R1-casp or GFP-IP(3)R1-ES can be used as a novel tool to deplete intracellular Ca(2+) stores.

Animals↗
PubMed2003

Age and anesthetic effects on murine electrocardiography.

Murine models offer potential insights regarding human cardiac disease, but efficient and reliable methods for phenotype evaluation are necessary. We employed non-invasive electrocardiography (ECG) in mice, investigating statistical reliability of these parameters with respect to anesthetic and animal age. Mice (C57BL/6, 8 or 48 weeks) were anesthetized by ketamine/xylazine (K/X, 80/10 mg/kg ip) or by inhalation anesthetic (halothane, HAL; sevoflurane, SEV) and 6 lead ECGs were recorded. P wave duration and QT interval was significantly prolonged with K/X compared to HAL and SEV, indicating slowed atrial and ventricular conduction. P-R interval (atrio-ventricular conduction) was significantly increased in aged mice under all anesthetics. Heart rate was inversely correlated to QT interval and P wave duration. We also detected significant age effects with respect to optimal approaches for QT interval corrections. Power analysis showed 4-fold higher number of mice/group, were required for K/X, to achieve identical statistical sensitivity. These data demonstrate the importance of anesthetic selection for relevant and reliable ECG analysis in mice and illustrate the selective influences of anesthetics and age on cardiac conductance in this species.

Aging↗
PubMed2003

Effects of changing heart rate on electrophysiological and hemodynamic function in the dog.

Cardiovascular parameters were measured in dogs after RR interval was changed from 0.25 s to 1.2 s with atropine and graded doses of zatebradine, an I(f)-channel blocker. Left ventricular (LV) pre-ejection period (PEP), systemic vascular resistance, tau (an estimate of myocardial stiffness), PQ, QTc, dLVP/dt(max) and dLVP/dt(min), aortic pressure, and right atrial pressure did not change when each parameter was plotted against RR interval (r(2)'s < or = 0.5). LV end-diastolic pressure, stroke volume index, LV ejection time (ET), and QT all increased either linearly or curvilinearly as RR interval prolonged. Cardiac output index and PEP/ET decreased curvilinearly. When heart rate (HR) was fixed by pacing, and graded doses of zatebradine were given, changes in cardiovascular function were minimal. Thus zatebradine affects cardiovascular function principally by changing HR and not by affecting function directly. This study provides data on the effects of changing HR, alone, on cardiovascular parameters measured frequently during pharmacological and toxicological studies. It should prove useful when physiological variables, including HR, change, and there is need to know what change in HR, alone, contributes.

Animals↗
PubMed2003

Graves' disease associated with anticardiolipin antibody positivity and acquired protein S deficiency.

A 33-year-old woman had experienced recurrent pregnancy loss. She had positive anticardiolipin antibody and protein S deficiency. Her pregnancy was managed with anticoagulant therapy and she delivered a healthy infant. Three years after delivery, she reported progressive sweating, tremor, tachycardia, and a 4-kg weight loss. She was diagnosed with Graves' disease. This is a rare case of combined anticardiolipin antibody positivity, acquired protein S deficiency, and Graves' disease.

Abortion, Spontaneous↗
PubMed2003

Leukocyte angiotensin II levels inpatients with essential hypertension:relation to insulin resistance.

Insulin resistance is involved in the pathogenesis of type 2 diabetes, hypertension, and atherosclerosis. Angiotensin (Ang) converting enzyme inhibitors and Ang II type 1 receptor antagonists improve insulin resistance in patients with essential hypertension, which suggest that tissue Ang II is involved in insulin resistance in patients with hypertension. To investigate the participation of tissue Ang II in insulin resistance associated with hypertension, we evaluated the Ang II-generating system in leukocytes and its relation to insulin resistance in patients with essential hypertension. Eighteen patients with essential hypertension participated in this study. Ang II was separated from leukocytes by reversed-phase high-performance liquid chromatography and measured by radioimmunoassay. Insulin resistance was evaluated by determining the steady-state of plasma glucose (SSPG) concentration. The Ang I- and Ang II-generating activities were evaluated in human leukocytes. Human leukocytes have Ang I- and Ang II-generating activities. The Ang II-generating activity was significantly inhibited by pepstatin A. Leukocyte Ang II level does not correlate with BP or plasma Ang II level in patients with essential hypertension. Leukocyte Ang II level strongly correlates with SSPG concentration, and significantly correlates with body mass index and plasma insulin, and with leptin levels in patients with essential hypertension. Leukocyte Ang II may be directly associated with insulin resistance.

Adult↗
PubMed2003

Haplotype analysis of the human renin gene and essential hypertension.

The human renin gene is an attractive candidate for involvement in the underlying cause of essential hypertension (EH). Despite extensive examination, the relation between the renin gene and hypertension remains unclear. The aims of the present study were to discover new genetic markers of EH and to investigate the relations between polymorphisms of the renin gene and EH in the Japanese. Using the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method, we isolated 3 novel variants of the renin gene; a single nucleotide polymorphism (SNP) in intron 4 (T+17int4G), a variable number of tandem repeats (VNTR) polymorphism in intron 7, and a missense mutation in exon 9 (G1051A). We performed an association study with these polymorphisms in 212 patients with EH and 209 age-matched normotensive (NT) subjects. The frequency of genotypes VNTR and T+17int4G did not differ significantly between the 2 groups, whereas the overall distribution of G1051A was significantly different between EH and NT. Haplotype analysis revealed that the overall distribution of haplotypes differed significantly between the EH and NT groups. PRA levels in patients with EH with the G/G genotype were significantly higher than in subjects with EH with G/A and A/A genotypes. These data suggest that the missense mutation in exon 9 may affect the enzymatic function of renin and consequently may be involved in the etiology of hypertension.

Adult↗
PubMed2003

A novel variable number of tandem repeat polymorphism of the renin gene and essential hypertension.

The aims of the present study were to find new genetic markers of essential hypertension (EH) and to investigate relationships between EH and polymorphisms of the renin gene. Using single strand conformation polymorphism, we discovered a new variable number of tandem repeat (VNTR) polymorphism in intron 7 that is 18 bp upstream from the boundary with exon 8. Nucleotide sequencing revealed that this VNTR polymorphism is a tandem repeat of the 4-nucleotide sequence TCTG. There were 6 alleles of this VNTR polymorphism, ranging from 7 repeats to 12 repeats. We analyzed the association between EH and this VNTR polymorphism. There was no significant difference in the overall distribution of this VNTR polymorphism between the EH and normotensive subjects. In summary, we discovered a novel VNTR polymorphism in the renin gene, and this polymorphism was not associated with EH.

Adult↗
PubMed2003

Haplotype analysis of the prostacyclin synthase gene and essential hypertension.

Previously, we discovered 3 polymorphisms in the prostacyclin synthase (PGIS) gene: 1) T-192G, in the 5-flanking region, a novel single-nucleotide polymorphism (SNP) that is not associated with essential hypertension (EH); 2) a variable number of tandem repeat (VNTR) polymorphism, 6 nucleotides upstream from the ATG start codon, that is associated with risk of cerebral infarction; and 3) C1117A, in exon 8, an SNP that does not cause an amino acid change in codon 373, and that is associated with risk of myocardial infarction (MI). The purpose of the present study was to establish haplotypes of the PGIS gene consisting of these 3 polymorphisms, and to assess the association between these haplotypes and EH. We detected 19 haplotypes. There was no significant difference in the overall distribution of haplotypes between EH and normotensive subjects. To summarize, we successfully identified haplotypes of the PGIS gene, and these haplotypes were not associated with EH.

Adult↗
PubMed2003

[A case of Fitz-Hugh-Curtis Syndrome representing hepatic capsular enhancement].

We present CT findings of a 22-year-old woman diagnosed as Fitz-Hugh-Curtis syndrome. The patient was admitted to our hospital with right upper abdominal pain. Abdominal enhanced CT showed hepatic capsular enhancement over the medial segment and the right lobe on the early phase. This capsular enhancement completely disappeared after treatment. Abdominal enhanced CT may serve as a non-invasive modality for the diagnosis of Fitz-Hugh-Curtis syndrome.

Abdominal Pain↗
PubMed2003

[Fitz-Hugh-Curtis syndrome: analysis of CT findings].

Fitz-Hugh-Curtis syndrome (FHCS) is a condition with right upper quadrant pain in association with pelvic inflammatory disease. Invasive procedures such as laparoscopy or laparotomy were indispensable to definite diagnosis of FHCS, and no more useful methods in radiological diagnosis of FHCS has been reported until now. In this present study abdominal enhanced-CT findings were analysed retrospectively in eight cases diagnosed clinically as FHCS. We focused on hepatic capsular enhancement, which was identified on early phase in all cases and on delayed phase in five. Moreover, hepatic capsular enhancement was detected at the anterior surface of medial segment and the lateral aspect of right lobe in all cases, while at the anterior surface of lateral segment in five cases. These findings, which disappeared on follow-up CT after treatment, were thought to reflect "acute" peri-hepatitis. Abdominal enhanced CT, especially on early phase, is suggested to be a non-invasive, useful modality for the diagnosis of FHCS. When hepatic capsular enhancement is identified in the interpretation of abdominal enhanced CT images in sexually active women who have right upper abdominal pain, we should suspect the possibility of FHCS and examine gynecological findings or the value of IgA and IgG antibodies for Chlamydia trachomatis.

Abdominal Pain↗
PubMed2002

Protein 4.1N is required for translocation of inositol 1,4,5-trisphosphate receptor type 1 to the basolateral membrane domain in polarized Madin-Darby canine kidney cells.

Protein 4.1N was identified as a binding molecule for the C-terminal cytoplasmic tail of inositol 1,4,5-trisphosphate receptor type 1 (IP(3)R1) using a yeast two-hybrid system. 4.1N and IP(3)R1 associate in both subconfluent and confluent Madin-Darby canine kidney (MDCK) cells, a well studied tight polarized epithelial cell line. In subconfluent MDCK cells, 4.1N is distributed in the cytoplasm and the nucleus; IP(3)R1 is localized in the cytoplasm. In confluent MDCK cells, both 4.1N and IP(3)R1 are predominantly translocated to the basolateral membrane domain, whereas 4.1R, the prototypical homologue of 4.1N, is localized at the tight junctions (Mattagajasingh, S. N., Huang, S. C., Hartenstein, J. S., and Benz, E. J., Jr. (2000) J. Biol. Chem. 275, 30573-30585), and other endoplasmic reticulum marker proteins are still present in the cytoplasm. Moreover, the 4.1N-binding region of IP(3)R1 is necessary and sufficient for the localization of IP(3)R1 at the basolateral membrane domain. A fragment of the IP(3)R1-binding region of 4.1N blocks the localization of co-expressed IP(3)R1 at the basolateral membrane domain. These data indicate that 4.1N is required for IP(3)R1 translocation to the basolateral membrane domain in polarized MDCK cells.

Animals↗
PubMed2002

Splicing mutation of the prostacyclin synthase gene in a family associated with hypertension.

Prostacyclin inhibits platelet aggregation, smooth muscle cell proliferation, and vasoconstriction. The prostacyclin synthase (PGIS) gene is a candidate gene for cardiovascular disease. The purpose of this study was to locate possible mutations in the PGIS gene related to hypertension and cerebral infarction. Using the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method, we discovered a T to C transition at the +2 position of the splicing donor site of intron 9 in patients with essential hypertension (EH). In vitro expression analysis of an allelic minigene consisting of exons 8-10 revealed that the nucleotide transition causes skipping of exon 9. This in turn alters the translational reading frame of exon 10 and introduces a premature stop codon (TGA). A three-dimensional model shows that the splice site mutation produces a truncated protein with a deletion in the heme-binding region. This splice site mutation was found in only one subject in 200 EH patients and 200 healthy controls. Analysis of the patient's family members revealed the mutation in two of the three siblings. The urinary excretion of prostacyclin metabolites in subjects with the mutation was significantly decreased. All subjects displaying the splice site mutation in the PGIS gene were hypertensive. In this study, we report a novel splicing mutation in the PGIS gene, which is associated with hypertension in a family. It is thought that this mechanism may involve in the pathophysiology of their hypertension.

Alleles↗
PubMed2002

Electrocardiographic and hemodynamic effects of cisapride alone and combined with erythromycin in anesthetized dogs.

The cardiovascular effects of cisapride administered intravenously at escalating doses with and without pretreatment with erythromycin were evaluated in morphine/chloralose anesthetized dogs. Dogs were instrumented to permit simultaneous recording of ECGs, left ventricular (LVP) and aortic (AoP) pressures, as well as programmed electrical stimulation (PES). Escalating intravenous doses of cisapride from 2 to 8 mg/kg (four times the recommended therapeutic dose) increased the heart rate (HR) and prolonged the corrected QT interval (QTc) (p < 0.05) compared to controls. Pretreatment with erythromycin failed to enhance the effect of cisapride on either HR or QTc. Cisapride with or without erythromycin pretreatment had no effect on AoP, but depressed indices of left ventricular contractility (dP/dt(max) decreased while PEP/ET increased) compared to controls. No dogs developed spontaneous arrhythmias, and arrhythmias were not inducible by PES. Cisapride with or without erythromycin pretreatment altered the orientation of the T-wave vector (p < 0.05) compared to controls, indicating a primary effect of cisapride on ventricular repolarization. The QTc and T wave changes observed were consistent with the known action of cisapride on canine I(Kr) channels.

Anesthesia, Intravenous↗
PubMed2002

Association of a novel single nucleotide polymorphism of the prostacyclin synthase gene with myocardial infarction.

BACKGROUND: Myocardial infarction (MI) is a complex multifactorial and polygenic disorder that is thought to result from an interaction between an individual's genetic makeup and various environmental factors. The purpose of this study was to investigate the association between a novel single nucleotide polymorphism in the prostacyclin synthase gene and MI. METHODS AND RESULTS: By the use of polymerase chain reaction-single-strand conformation polymorphism analysis, we identified a single nucleotide polymorphism, C1117A, in exon 8. This nucleotide change did not cause an amino acid change in codon 373. We performed an association study of the polymorphism in 138 patients and 130 healthy control subjects. Multiple logistic linear regression analysis showed the genotype distributions were significantly different between the control group and the MI group (odds ratio, 2.12; 95% CI, 1.47-3.05, P =.04). The C/C genotype was found more frequently in the MI group than in the control group. CONCLUSIONS: We conclude that the C1117A polymorphism in exon 8 is associated with risk for MI and may be a genetic marker of MI in Japanese persons.

Case-Control Studies↗
PubMed2002

Angiotensin-converting enzyme gene and longevity in the Xin Jiang Uighur autonomous region of China: an association study.

BACKGROUND: Longevity can be regarded as a multifactorial trait that results from an interaction between environmental factors and sets of epistatic alleles that have pleiotropic age-dependent effects. The Hotan district in the Xin Jiang Uighur Autonomous region of China is relatively isolated and is well known for an ethnic group that displays marked longevity. METHODS: We performed a correlation study between the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene and longevity by comparing distributions of the polymorphism between three different ethnic groups in this region. We obtained data from 424 subjects comprising 227 Uighur individuals, 108 Kazakh individuals, and 89 Han individuals. All subjects in the latter two groups ranged in age from 65 to 70 years, whereas the Uighur subjects actually comprised two different age groups: those ranging in age from 59 to 70 years (Uighur older group in Hotan [UOH]) and those ranging in age from 90 to 113 years (Uighur longevity group in Hotan [ULH]). Genomic DNA was extracted from peripheral white blood cells. Polymerase chain reaction was performed to amplify the I/D polymorphic region of the ACE gene. RESULTS: Frequencies of the insertion (I) and deletion (D) alleles were 0.596 (243/408) and 0.404 (165/408) in the Uighur group, 0.606 (130/216) and 0.394 (85/216) in the Kazakh group, and 0.657 (117/178) and 0.343 (61/178) in the Han group. The overall distributions of alleles in these three groups did not differ significantly (chi(2) = 4.6, p =.33). Within the Uighur group, frequency of the D allele was significantly higher in the ULH group (0.448) than in the UOH group (0.355) (p <.04). CONCLUSIONS: This association reflects a genetic influence on differential survival and may point to pleiotropic age-dependent effects on longevity. Our data may help elucidate the relationship between natural longevity and race difference among individuals in the Xin Jiang Uighur Autonomous region of China.

Aged↗
PubMed2002

Ambulatory blood pressure monitoring in Uygur centenarians.

Cross-sectional surveillance was carried out in long-lived Uygur in China to investigate blood pressure (BP) and pulse rate (PR) variation in centenarians. The study group comprised 33 centenarians (age > or = 100 years), 103 longevous subjects (age 90-99 years) and 100 elderly (age 65-70 years) subjects. Office BP was measured, and 24-h noninvasive ambulatory blood pressure monitoring (ABPM) was performed. The office BP was higher and hypertension occurred more frequently in the centenarians than in either the longevous or elderly subjects. Mean 24-h systolic and diastolic BP was higher in the centenarians than in the other 2 groups. However, mean 24-h PR did not differ between them. Day-night differences in systolic BP decreased, and the non-dipper-type BP pattern was common in the centenarians (79.1% vs 68% and 63.6% in longevous and elderly subjects, respectively). Circadian BP was characterized by 3 peaks in longevous subjects and multiple peaks in centenarians. Morning rising and nocturnal dipping of BP were observed in both longevous and elderly subjects. In conclusion, BP in longevous and elderly Uygur was characterized by circadian rhythmicity, but the nocturnal fall in BP was not seen in centenarians. Differences in day-night BP and circadian rhythmicity may decrease with advancing age, especially in centenarians.

Aged↗