PBRM1 loss in porocarcinoma arising from poroma.
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Letter↗
Biomedical subjects
K Nakamura
Publications and source records attributed to K Nakamura.
Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport and metabolism in human pancreatic cancer cells.
To identify predictive molecular markers for gemcitabine resistance, we investigated changes in the expression of four genes associated with gemcitabine transport and metabolism during the development of acquired gemcitabine resistance of pancreatic cancer cell lines. The expression levels of human equilibrative nucleoside transporter-1 (hENT1), deoxycytidine kinase (dCK), RRM1, and RRM2 mRNA were analysed by real-time light cycler-PCR in various subclones during the development of acquired resistance to gemcitabine. Real-time light cycler-PCR demonstrated that the expression levels of either RRM1 or RRM2 progressively increased during the development of gemcitabine resistance. Expression of dCK was slightly increased in cells resistant to lower concentrations of gemcitabine, but was decreased below the undetectable level in higher concentration-resistant subclones. Expression of hENT1 was increased in the development of gemcitabine resistance. As acquired resistance to gemcitabine seems to correlate with the balance of these four factors, we calculated the ratio of hENT1 x dCK/RRM1 x RRM2 gene expression in gemcitabine-resistant subclones. The ratio of gene expression decreased progressively with development of acquired resistance in gemcitabine-resistant subclones. Furthermore, the expression ratio significantly correlated with gemcitabine sensitivity in eight pancreatic cancer cell lines, whereas no single gene expression level correlated with the sensitivity. These results suggest that the sensitivity of pancreatic cancer cells to gemcitabine is determined by the ratio of four factors involved in gemcitabine transport and metabolism. The ratio of the four gene expression levels correlates with acquired gemcitabine-resistance in pancreatic cancer cells, and may be useful as a predictive marker for the efficacy of gemcitabine therapy in pancreatic cancer patients.
Antimetabolites, Antineoplastic↗
Role of postprandial hyperglycaemia in cardiovascular disease in diabetes.
Diabetes is associated with a marked increase in the risk of atherosclerotic vascular disorders, including coronary, cerebrovascular and peripheral artery disease. Cardiovascular disease (CVD) could account for disabilities and high mortality rates in patients with diabetes. Conventional risk factors, including hyperlipidaemia, hypertension, smoking, obesity, lack of exercise and a positive family history, contribute similarly to macrovascular complications in type 2 diabetic patients and non-diabetic subjects. The levels of these factors in diabetic patients are certainly increased, but not enough to explain the exaggerated risk for macrovascular complications in diabetic population. Therefore, specific diabetes-related risk factors should be involved in the excess risk in diabetic patients. In this paper, we review the molecular mechanisms for accelerated atherosclerosis in diabetes, especially focusing on postprandial hyperglycaemia. We also discuss here the potential therapeutic strategy that specifically targets CVD in patients with diabetes.
Diabetes Mellitus, Type 2↗
Prevention of diabetic vascular calcification by nifedipine, a dihydropyridine-based calcium channel blocker.
Vascular calcification is a common feature in advanced atherosclerosis and also a predictor of future cardiovascular events such as unstable angina and myocardial infarction, especially in diabetes. There is a growing body of evidence that advanced glycation end products (AGEs), senescent macroprotein derivatives formed at an accelerated rate in diabetes, exist within atherosclerotic lesions, thereby being implicated in the pathogenesis of accelerated atherosclerosis in diabetes. Indeed, we have previously shown that AGE - their receptor (RAGE) interaction could induce angiogenesis through autocrine production of vascular endothelial growth factor, suggesting its role for plaque formation and enlargement in diabetes. Furthermore, we have found that AGEs have the ability to induce the osteoblatic differentiation of pericytes, thus contributing to the development of vascular calcification as well. These observations suggest that the inhibition of AGE formation or blockade of the downstream signaling of RAGE may be a novel therapeutic target for the inhibition of vascular calcification in diabetic atherosclerosis. Since we, along with others, have shown that nifedipine inhibits glycation of low-density lipoprotein in vitro and blocks the AGE-induced RAGE expression in endothelial cells through its anti-oxidative properties, nifedipine could inhibit vascular calcification by blocking the AGE formation or the downstream signaling in diabetes. In this paper, we would like to propose the possible ways of testing our hypothesis. Does nifedipine treatment slow down the progression of coronary calcification in diabetic patients? If the answer is yes, is this beneficial effect of nifedipine superior to that of other DHPs with equihypotensive properties? Does nifedipine treatment decrease expression levels of AGEs and RAGE in diabetic atherosclerosis? Is the unique effect of nifedipine on vascular calcification correlated with its AGE or RAGE-suppressing properties? These prospective studies will provide further valuable information whether nifedipine could prevent vascular calcification in diabetic atherosclerosis by blockade the AGE-RAGE signaling in vascular wall cells.
Calcinosis↗
Mitogenomic evolution and interrelationships of the Cypriniformes (Actinopterygii: Ostariophysi): the first evidence toward resolution of higher-level relationships of the world's largest freshwater fish clade based on 59 whole mitogenome sequences.
Fishes of the order Cypriniformes are almost completely restricted to freshwater bodies and number > 3400 species placed in 5 families, each with poorly defined subfamilies and/or tribes. The present study represents the first attempt toward resolution of the higher-level relationships of the world's largest freshwater-fish clade based on whole mitochondrial (mt) genome sequences from 53 cypriniforms (including 46 newly determined sequences) plus 6 outgroups. Unambiguously aligned, concatenated mt genome sequences (14,563 bp) were divided into 5 partitions (first, second, and third codon positions of the protein-coding genes, rRNA genes, and tRNA genes), and partitioned Bayesian analyses were conducted, with protein-coding genes being treated in 3 different manners (all positions included; third codon positions converted into purine [R] and pyrimidine [Y] [RY-coding]; third codon positions excluded). The resultant phylogenies strongly supported monophyly of the Cypriniformes as well as that of the families Cyprinidae, Catostomidae, and a clade comprising Balitoridae + Cobitidae, with the 2 latter loach families being reciprocally paraphyletic. Although all of the data sets yielded nearly identical tree topologies with regard to the shallower relationships, deeper relationships among the 4 major clades (the above 3 major clades plus Gyrinocheilidae, represented by a single species Gyrinocheilus aymonieri in this study), were incongruent depending on the data sets. Treatment of the rapidly saturated third codon-position transitions appeared to be a source of such incongruities, and we advocate that RY-coding, which takes only transversions into account, effectively removes this likely "noise" from the data set and avoids the apparent lack of signal by retaining all available positions in the data set.
Animals↗
Prognostic significance of stromal versican expression in human endometrial cancer.
BACKGROUND: Versican expression may enhance tumor invasion and metastasis. However, the expression of versican in human endometrial cancer has seldom been characterized. The aim of this study was to investigate versican expression in endometrial cancers. PATIENTS AND METHODS: We immunohistochemically investigated the expression of versican protein in 167 endometrial cancers and analyzed the correlation with various observed clinicopathological features, including patient outcome. RESULTS: Stromal versican expression was significantly higher in the advanced-stage (P = 0.010) and high-grade (P = 0.049) cancers, lymph node metastasis (P = 0.012), and ovarian metastasis (P = 0.024). Epithelial versican expression was significantly higher in patients with lymph node metastasis (P = 0.014) and lymph-vascular space involvement (P = 0.014). The disease-free survival (DFS) and overall survival (OS) rates of patients exhibiting high stromal versican expression were significantly lower than those of patients exhibiting low stromal versican expression (P < 0.0001). Multivariate analysis showed that high stromal versican expression was an independent prognostic factor for DFS and OS. CONCLUSIONS: Versican enrichment of the stroma may be associated with tumor progression in endometrial cancer. Stromal versican expression can serve as an indicator of poor prognosis for patients with endometrial cancer.
Adenocarcinoma↗
Measurement of atmospheric neutrino flux consistent with tau neutrino appearance.
A search for the appearance of tau neutrinos from nu(mu) <--> nu(tau) oscillations in the atmospheric neutrinos has been performed using 1489.2 days of atmospheric neutrino data from the Super-Kamiokande-I experiment. A best fit tau neutrino appearance signal of 138+/-48(stat)-32(+15)(syst) events is obtained with an expectation of 78+/-26(syst). The hypothesis of no tau neutrino appearance is disfavored by 2.4 sigma.
Journal Article↗
Association of CXCR4 and CCR7 chemokine receptor expression and lymph node metastasis in human cervical cancer.
BACKGROUND: The chemokine receptors CXCR4 and CCR7 have been suggested to play an important role in cancer invasion and metastasis. The expression of these receptors in human cervical cancer, however, has seldom been characterized. PATIENTS AND METHODS: We investigated the expression of CXCR4 and CCR7 in cervical cancer specimens and determined the association between their expression and the clinicopathological features observed, including patient outcome. RESULTS: CXCR4 expression was significantly higher in elderly patients (P=0.025); it was also significantly increased in patients with cancers displaying large tumor size (P=0.010), deep stromal invasion (P=0.0004), lymph-vascular space involvement (P=0.0002), or lymph node metastasis (P<0.0001). CCR7 expression was significantly higher in cases of squamous cell carcinomas (P=0.010) and in patients with cancers showing large tumor size (P<0.0001), deep stromal invasion (P<0.0001), vaginal invasion (P=0.047), lymph-vascular space involvement (P=0.012), or lymph node metastasis (P<0.0001). Logistic regression analysis revealed that deep stromal invasion (P=0.017) and CXCR4 (P=0.016) and CCR7 (P=0.022) expression were independent factors that influenced pelvic lymph node metastasis. The disease-free survival and overall survival (OS) rates of patients exhibiting both CXCR4 and CCR7 expression were significantly reduced (P<0.0001). In addition, the expression of both CXCR4 and CCR7 was an independent prognostic factor for OS (95% confidence interval=1.03-17.86; P=0.046). CONCLUSIONS: CXCR4 and CCR7 expression may be associated with lymph node metastasis; moreover, the expression of these receptors can serve as an indicator of poor prognosis in patients with cervical cancer.
Adult↗
Revival of nifedipine, a dihydropyridine-based calcium blocker.
A recent analysis by the Blood Pressure Lowering Treatment Trialists' Collaboration revealed that any commonly-used blood pressure (BP)-lowering regimen reduced the risk of total major cardiovascular events, and larger reductions in BP produced larger reductions in the risk. These observations suggest that most of the differences among treatment regimens in their effects on cardiovascular outcomes could be explained by the differences in achieved BP level. However, it may also be true that some treatment regimen is superior or inferior to others with regard to the risk reduction of cardiovascular events. Indeed, the data from dihydropyridine-based calcium antagonist (DHP) trails are consistent in that they could not protect against new-onset heart failure or progression of renal disease in patients with left-ventricular systolic dysfunction or overt proteinuria, respectively. However, a multicenter, randomized, placebo-controlled, double-blind ACTION trial, which compared the effect of long-acting nifedipine or placebo on mortality and cardiovascular morbidity in patients with stable angina, revealed that nifedipine reduced the risk for new-onset overt heart failure by 29%. Further, an open-label, randomized prospective J-MIND trial, which compared the effect of long-acting nifedipine or enalapril, an angiotensin-converting enzyme inhibitor on onset and progression of nephropathy in hypertensive patients with type 2 diabetes, showed that long-acting nifedipine had an equipotent reoprotective effect on diabetic nephropathy. In this paper, we would like to propose our hypothesis that nifedipine may be unique and superior in its effects on heart failure and proteinuria compared with various DHPs. For ensuring our hypothesis, the following clinical issues would be addressed. Does nifedipine treatment alone decrease the progression of renal disease with overt proteinuria? If these answers are yes, are these beneficial effects of nifedipine superior to that of other DHPs with equihypotensive properties? Does nifedipine treatment also reduce oxidative stress markers? Are these unique effects of nifedipine correlated with its anti-oxidative properties? These prospective studies will provide further valuable information whether nifedipine may be a preferred DHP to achieve BP goals in hypertensive patients with systolic dysfunction or overt proteinuria.
Angina Pectoris↗
Telmisartan inhibits AGE-induced C-reactive protein production through downregulation of the receptor for AGE via peroxisome proliferator-activated receptor-gamma activation.
AIMS/HYPOTHESIS: C-reactive protein (CRP), an acute-phase reactant produced mainly by the liver, is elevated in diabetes, thus contributing to the development and progression of atherosclerosis. However, the molecular mechanism underlying the elevation of CRP in diabetes is not fully understood. Since a crosstalk between AGE and angiotensin II (Ang II) has been proposed in the pathogenesis of accelerated atherosclerosis in diabetes, we examined here whether and how telmisartan, a unique Ang II type 1 receptor blocker (ARB) with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-modulating activity, could inhibit AGE-induced CRP expression in a human hepatoma cell line, Hep3B cells. METHODS: Protein levels of the receptor for AGE (RAGE) were analysed by western blots. Gene expression was analysed by quantitative real-time RT-PCR. CRP released into the medium was measured with ELISA. Intracellular formation of reactive oxygen species (ROS) was measured using the fluorescent probe CM-H(2)DCFDA. RESULTS: Telmisartan, but not candesartan, another ARB, downregulated RAGE mRNA levels in a dose-dependent manner. Telmisartan decreased basal as well as AGE-induced RAGE protein expression in Hep3B cells. Furthermore, telmisartan dose-dependently inhibited AGE-induced ROS generation and subsequent CRP gene and protein induction in Hep3B cells. GW9662, an inhibitor of PPAR-gamma, blocked the inhibitory effects of telmisartan on RAGE expression and its downstream signalling in Hep3B cells. CONCLUSIONS/INTERPRETATION: Our present study indicates a unique beneficial aspect of telmisartan: it may work as an anti-inflammatory agent against AGE by suppressing RAGE expression via PPAR-gamma activation in the liver and may play a protective role in vascular injury in diabetes.
Benzimidazoles↗
Frontal cerebral blood flow change associated with infant-directed speech.
OBJECTIVE: To examine the auditory perception of maternal utterances by neonates using near-infrared spectroscopy (NIRS). METHODS: Twenty full-term, healthy neonates were included in this study. The neonates were tested in their cribs while they slept in a silent room. First, two probe holders were placed on the left and right sides of the forehead over the eyebrows using double-sided adhesive tape. The neonates were then exposed to auditory stimuli in the form of infant-directed speech (IDS) or adult-directed speech (ADS), sampled from each of the mothers, through an external auditory speaker. RESULTS: A 2 (stimulus: IDS and ADS) x 2 (recording site: channel 1 (right side) and channel 2 (left side)) analysis of variance for these relative oxygenated haemoglobin values showed that IDS (Mean = 0.25) increased brain function significantly (F = 3.51) more than ADS (Mean = -0.26). CONCLUSIONS: IDS significantly increased brain function compared with ADS. These results suggest that the emotional tone of maternal utterances could have a role in activating the brains of neonates to attend to the utterances, even while sleeping.
Acoustic Stimulation↗
Neuroprotection by PlGF gene-modified human mesenchymal stem cells after cerebral ischaemia.
Intravenous delivery of mesenchymal stem cells (MSCs) prepared from adult bone marrow reduces infarction size and ameliorates functional deficits in rat cerebral ischaemia models. Placental growth factor (PlGF) is angiogenic to impaired non-neural tissue. To test the hypothesis that PlGF contributes to the therapeutic benefits of MSC delivery in cerebral ischaemia, we compared the efficacy of systemic delivery of human MSCs (hMSCs) and hMSCs transfected with a fibre-mutant F/RGD adenovirus vector with a PlGF gene (PlGF-hMSCs). A permanent middle cerebral artery occlusion (MCAO) was induced by intraluminal vascular occlusion with a microfilament. hMSCs and PlGF-hMSCs were intravenously injected into the rats 3 h after MCAO. Lesion size was assessed at 3 and 6 h, and 1, 3, 4 and 7 days using MR imaging and histology. Functional outcome was assessed using the limb placement test and the treadmill stress test. Both hMSCs and PlGF-hMSCs reduced lesion volume, induced angiogenesis and elicited functional improvement compared with the control sham group, but the effect was greater in the PlGF-hMSC group. Enzyme-linked immunosorbent assay of the infarcted hemisphere revealed an increase in PlGF in both hMSC groups, but a greater increase in the PlGF-hMSC group. These data support the hypothesis that PlGF contributes to neuroprotection and angiogenesis in cerebral ischaemia, and cellular delivery of PlGF to the brain can be achieved by intravenous delivery of hMSCs.
Adenoviridae↗
Activity-dependent conduction block in multifocal motor neuropathy: magnetic fatigue test.
BACKGROUND: Multifocal motor neuropathy (MMN) is often misdiagnosed as motor neuron disease, especially when overt evidence of conduction block (CB) is lacking. Activity-dependent CB (ADCB), defined as transient CB induced by brief exercise, has been recently found in MMN but not in ALS. METHODS: To test the diagnostic utility of ADCB for differentiating MMN from ALS, the authors recorded the compound muscle action potentials (CMAPs) from small hand muscles by magnetically stimulating nerve roots before and after 1 minute of maximal voluntary contraction (magnetic fatigue test). They examined nine patients with MMN with unequivocal clinical responses to IV immunoglobulins (IVIgs), yet lacked CB according to the conventional criteria. RESULTS: Six MMN patients had postexercise CB/temporal dispersion maximum in the immediate postexercise period. ADCB in an MMN patient improved after IVIg. Further analysis revealed that prolongation of the duration from the onset to the positive peak of the CMAP was the most sensitive indicator for MMN, presumably because the phase cancellation obscures the abnormalities of the other parameters. CONCLUSION: The magnetic fatigue test is useful in detecting mild conduction block presumably located in a proximal nerve segment in patients with multifocal motor neuropathy who do not fulfill its conventional electrodiagnostic criteria.
Adult↗
Genetic characterization of Batai virus indicates a genomic reassortment between orthobunyaviruses in nature.
Two viruses were isolated from bovine blood in the southernmost part of Japan in 1994 and 2001, respectively. Genetic analyses showed that the viruses were Batai virus of the genus Orthobunyavirus of the family Bunyaviridae. The sequencing of three genomic RNA segments of the Japanese and Malaysian Batai virus strains revealed that the M RNA segment of Batai virus had high sequence identity with that of Ngari virus. Our results indicate that Ngari virus is a genetic reassortant with S and L RNA segments from Bunyamwera virus and an M RNA segment from Batai virus.
Animals↗
Correlation between national income, HIV/AIDS and political status and mortalities in African countries.
OBJECTIVES: To investigate associations between mortalities in African countries and problems that emerged in Africa in the 1990s (reduction of national income, HIV/AIDS and political instability) by adjusting for the influences of development, sanitation and education. METHODS: We compiled country-level indicators of mortalities, national net income (the reduction of national income by the debt), infection rate of HIV/AIDS, political instability, demography, education, sanitation and infrastructure, from 1990 to 2000 of all African countries (n=53). To extract major factors from indicators of the latter four categories, we carried out principal component analysis. We used multiple regression analysis to examine the associations between mortality indicators and national net income per capita, infection rate of HIV/AIDS, and political instability by adjusting the influence of other possible mortality determinants. RESULTS: Mean of infant mortality per 1000 live births (IMR); maternal mortality per 100,000 live birth (MMR); adult female mortality per 1000 population (AMRF); adult male mortality per 1000 population (AMRM); and life expectancy at birth (LE) in 2000 were 83, 733, 381, 435, and 51, respectively. Three factors were identified as major influences on development: education, sanitation and infrastructure. National net income per capita showed independent negative associations with MMR and AMRF, and a positive association with LE. Infection rate of HIV/AIDS was independently positively associated with AMRM and AMRF, and negatively associated with LE in 2000. Political instability score was independently positively associated with MMR. CONCLUSIONS: National net income per capita, HIV/AIDS and political status were predictors of mortality indicators in African countries. This study provided evidence for supporting health policies that take economic and political stability into account.
Africa↗
Phase II trial of oral S-1 combined with gemcitabine in metastatic pancreatic cancer.
We conducted a phase II trial of gemcitabine with S-1, oral fluorouracil (5-FU) prodrug tegafur combined with two modulators, 5-chloro-2, 4-dihydroxypyridine and potassium oxonate, to evaluate the activity and toxicity of such a combination in metastatic pancreatic cancer (MPC) patients. Patients who had pathologically proven pancreatic cancer with metastatic lesions were eligible candidates for entry into the study. S-1 was given orally (30 mg m(-2)) b.i.d. for 14 consecutive days and gemcitabine (1000 mg m(-2)) was given on days 8 and 15. The cycle was repeated every 21 days. We enrolled 33 MPC patients. The median number of cycles was eight (range 1-20). Grade 3-4 toxicities were leucopenia (33%), neutropenia (55%), anaemia (9%), thrombocytopenia (15%), anorexia (6%), fever (9%), and interstitial pneumonia (6%). Objective responses were obtained in 16 patients (one complete response and 15 partial responses; response rate, 48%; 95% confidence interval (CI), 33-65). Median survival and 1-year survival rate were 12.5 months (95% CI, 5.9-19.1) and 54% (95% CI, 36-72), respectively. Combination chemotherapy with GEM and S-1 was well tolerated and yielded a significantly high response rate.
Aged↗
Endoscopic band ligation therapy for upper gastrointestinal bleeding related to Mallory-Weiss syndrome.
BACKGROUND: No consensus exists as to the best endoscopic treatment for Mallory-Weiss syndrome. Endoscopic band ligation is a readily available and easily learned technique. This prospective study evaluated the efficacy and safety of endoscopic band ligation therapy for Mallory-Weiss syndrome. METHODS: From August 1998 to June 2005, a clinical trial assessed 37 patients with a diagnosis of Mallory-Weiss syndrome who had active bleeding, exposed vessels, or both. Their lesions were treated using endoscopic band ligation. RESULTS: Endoscopic band ligation was successful in 36 of 37 cases, with a follow-up period ranging from 1 to 24 months. The remaining patient had severe liver failure and disseminated intravascular coagulation. The patient bled again at 12 h and subsequently died. Except for this case, no recurrent bleeding, perforation, or other complications occurred. CONCLUSIONS: The study results suggest that endoscopic band ligation is an effective, safe, and easily learned procedure for treating upper gastrointestinal bleeding related to Mallory-Weiss syndrome.
Adult↗
Correlations between bone mineral density and demographic, lifestyle, and biochemical variables in community-dwelling Japanese women 69 years of age and over.
INTRODUCTION: A few epidemiologic studies have comprehensively attempted to identify risk factors for low bone mineral density (BMD) in elderly Asian women. The purpose of this study was to identify demographic, lifestyle, and biochemical factors correlated with BMD in elderly Japanese women 69 years of age and over. METHODS: The study design was cross-sectional. The subjects were 583 ambulatory women aged 69 years and over, and their average age was 74.3 (SD 4.4) years. Predictor variables were age, reproductive history, anthropometric indices, grip strength, calcium intake, lifestyle information, and serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D (1,25(OH)(2)D), osteocalcin (OC), and undercarboxylated osteocalcin (ucOC) values. The outcome variable was forearm BMD measured with a DTX-200 osteometer. RESULTS: Simple linear regression analyses showed that BMD was significantly positively associated with body height, weight, body mass index, grip strength, serum albumin concentration, and "housework," and negatively associated with age, years since menopause, age at menarche, number of children, serum 1,25(OH)(2)D concentration, serum OC concentration, and ucOC concentration. The stepwise multiple regression analysis showed that weight (beta=0.00316, SE=0.00028, R(2)=0.180), age (beta=-0.00321, SE=0.00050, R(2)=0.108), log-transformed serum OC (beta=-0.0445, SE=0.0064, R(2)=0.053), log-transformed serum 1,25(OH)(2)D (beta=-0.0401, SE=0.0074, R(2)=0.050), "farmwork" (beta=0.00904, SE=0.00426, R(2)=0.005), and serum 25(OH)D concentration (beta=0.000281, SE=0.000120, R(2)=0.003) were significantly associated with BMD. CONCLUSION: It was concluded that body weight is a major predictor of forearm BMD among the factors measured in this study in independent Japanese women 69 years of age and over and that serum 1,25(OH)(2)D concentration may be associated with cortical BMD. Maintenance of body weight is very important for maintaining BMD in this population, unless a large weight aggravates obesity-related diseases. A follow-up study is needed to confirm these findings.
25-Hydroxyvitamin D 2↗