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R Chen

Publications and source records attributed to R Chen.

At least 19 recordsLinked to original sources
PubMed2026

Development of RS1-specific ACMG/AMP variant classification criteria with pilot variant curation.

Gene-based therapies are being developed for retinal diseases, including RS1-related X-linked retinoschisis. Therefore it is essential to determine which variants are pathogenic and which are benign when enrolling patients. The Clinical Genome Resource (ClinGen) X-Linked Inherited Retinal Diseases (XLRD) Variant Curation Expert Panel (VCEP) brings together clinician scientists, molecular biologists, and geneticists to apply their expertise and review the clinical, genetic, population, and functional evidence for variants. American College of Medical Genetics (ACMG) guidelines have been modified for RS1 to develop a highly systematic and conservative framework for evaluating variants. The curation process involves applying 28 different codes, each with 4 strength levels (very strong, strong, moderate, supporting) across different domains of phenotype, population data, computational assessment, functional impact, and segregation. With RS1-specific rules, a total of 54 pilot variants were tested. These included 47 variants in ClinVar. Of these 21 variants were re-classified: 2 likely pathogenic variants and one likely benign were changed to variants of uncertain significance and 4 previously unclassified variants were changed to pathogenic, likely pathogenic and likely benign. Other changes resolved conflicts or multiple classifications.

Humans↗
PubMed2025

HLA-E and NKG2A Mediate Resistance to BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer.

Bacillus Calmette-Guérin (BCG) is the first-line therapy for high-grade non-muscle-invasive bladder cancer (NMIBC), yet many patients experience recurrence due to immune evasion. We identify HLA-E and NKG2A as mediators of adaptive resistance involving chronic activation of NK and T cells in BCG-unresponsive tumors. Prolonged IFN-γ exposure enhances HLA-E and PD-L1 expression on recurrent tumors, accompanied by the accumulation of NKG2A+ NK and CD8 T cells. HLA-Ehigh tumor cells preferentially cluster near CXCL12-rich stromal regions with dense effector cell presence, underscoring a spatially segregated tumor architecture. Although cytotoxic lymphocytes retain effector potential, their activity is restrained by HLA-E/NKG2A and PD-L1/PD-1 pathways located in their immediate neighborhood within the bladder tumor microenvironment. These data reveal a spatially organized immune escape program that limits anti-tumor immunity. Our findings support dually targeting NKG2A and PD-L1 checkpoint blockade as a rational, bladder-sparing strategy for patients with BCG-unresponsive NMIBC.

BCG-unresponsive↗
PubMed2007

Trophoblast-macrophage interactions: a regulatory network for the protection of pregnancy.

PROBLEM: Macrophages are one of the first immune cells observed at the implantation site. Their presence has been explained as the result of an immune response toward paternal antigens. The mechanisms regulating monocyte migration and differentiation at the implantation site are largely unknown. In the present study, we demonstrate that trophoblast cells regulate monocyte migration and differentiation. We propose that trophoblast cells 'educate' monocytes/macrophages to create an adequate environment that promote trophoblast survival. METHOD OF STUDY: CD14(+) monocytes were isolated from peripheral blood using magnetic beads. Co-culture experiments were conducted using a two-chamber system. Monocytes were stimulated with lipopolysaccharide (LPS) and cytokine levels were determined using multiplex cytokine detecting assay. RESULTS: Trophoblast cells increase monocyte migration and induce a significant increase in the secretion and production of the pro-inflammatory cytokines [interleukin-6 (IL-6), IL-8, tumor necrosis factor-alpha] and chemokines (growth-related oncogen-alpha, monocyte chemoattractant protein-1, macrophage inflammatory protein-1beta, RANTES). Furthermore, the response of monocytes to LPS was different in monocytes pre-exposed to trophoblast cells. CONCLUSION: The results of this study suggest that trophoblast cells are able to recruit and successfully educate monocytes to produce and secrete a pro-inflammatory cytokine and chemokine profile supporting its growth and survival. Furthermore we demonstrate that trophoblast cells can modulate monocytes response to bacterial stimuli.

Cell Communication↗
PubMed2006

Depot-specific messenger RNA expression of 11 beta-hydroxysteroid dehydrogenase type 1 and leptin in adipose tissue of children and adults.

OBJECTIVE: To compare expression of messenger RNA (mRNA) coding for the cortisol regenerating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), and the adipocytokines leptin and resistin in paired biopsies of subcutaneous adipose tissue (SC) and omental adipose tissue (OM) from children. DESIGN: Paired biopsies (SC and OM) were obtained from 54 children (age 0.17-16 years, body mass index (BMI) 12.5-28.3 kg/m(2), BMI standard deviation score (SDS) -2.5-4.5) and 16 adults (age 27-79 years, BMI 19-46 kg/m(2)) undergoing open abdominal surgery. mRNA levels of 11beta-HSD1, leptin and resistin were measured using quantitative real-time polymerase chain reaction (PCR). RESULTS: 11beta-HSD1 mRNA level was higher in OM than in SC (P<0.05), whereas leptin mRNA was higher in SC than in OM (P<0.001). There was no difference in the resistin mRNA level between SC and OM. These results were consistent in children and adults. In children, 11beta-HSD1 mRNA in SC was positively associated with BMI SDS (P<0.05), whereas in OM it was positively associated with age (P<0.05). The association between 11beta-HSD1 expression and age remained significant after adjustment for BMI SDS and gender. Leptin mRNA was positively associated with BMI SDS (SC: P<0.001, OM: P<0.001) but not with age in children. In multiple regression analyses, including anthropometric variables and age, BMI SDS was independently associated with mRNA levels of 11beta-HSD1 (P<0.05) and leptin (P<0.001) in SC. When normal weight and overweight children were analyzed separately, 11beta-HSD1 mRNA levels were positively associated with leptin in OM in the overweight group (P<0.05). CONCLUSION: There are depot-specific differences in mRNA levels of 11beta-HSD1 and leptin in children and adults. The positive association of 11beta-HSD1 mRNA in OM with age may reflect a causal role in visceral fat accumulation during growth. Increasing 11beta-HSD1 and leptin mRNA in SC with increasing BMI SDS could suggest that the risk of metabolic consequences of obesity may be established early in life.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2006

Reduced semen quality in chronic prostatitis patients that induce the release of apoptotic protein Omi/HtrA2 from spermatozoa.

The relationship between chronic prostatitis and fertility has been disputed for many years. Several groups have shown infection and autoimmune response against prostate antigens could have a deleterious effect on semen quality and fertility. This study was conducted to test the hypothesis that Omi/HtrA2-induced apoptosis in chronic prostatitis could be a mechanism underlying the observed clinical benefit. The Omi/HtrA2 serine protease is a nuclear-encoded mitochondrial protein, which can be released from mitochondria into the cytosol after apoptosis stimuli, inducing apoptosis in caspase-dependent and independent manners. Forty-one patients diagnosed as suffering from chronic prostatitis were included. Healthy normal individuals were included as controls. Human spermatozoa in the semen were purified by Percoll-gradient technique to separate the seminal plasma and other round cells. Measurements for sperm concentration, motility, morphology, proinflammatory cytokines, Omi/HtrA2 mRNA and protein levels in spermatozoa of chronic protatitis patients, were performed accordingly. Significantly increased levels of proinflammatory cytokines were detected in seminal plasma from these prostatitis patients. Omi/HtrA2 mRNA and protein levels were significantly higher in prostatitis men than in normal men. This study shows that chronic prostatitis patients present important alterations in their semen quality parameters, Omi/HtrA2 mRNA and protein levels of spermatozoa. We speculate that the inflammatory process involved may affect male fertility by release of proapoptotic protein Omi/HtrA2.

Adolescent↗
PubMed2006

Optical and dosimetric properties of zircon.

Irradiation effects were investigated in zircon crystals by methods of optical absorption and luminescence. Special attention was given to the effects of vacuum ultraviolet (VUV) radiation. The same main thermoluminescence (TL) peaks with the same thermal activation energies appeared after VUV as after X- or beta irradiation, indicating that the same traps were induced by the different irradiations. TL excitation spectra in the VUV showed an increase <220 nm and maxima near 190 and 140 nm. Excitation spectra of phototransferred TL (PTTL) and optically stimulated luminescence (OSL) were also measured. Most TL emission bands also appeared in the X-luminescence, PTTL and OSL. Dosimetric properties such as the TL radiation sensitivity, thermal stability of radiation-induced defects and TL dose dependence were also investigated. The radiation sensitivity of zircon was by an order of magnitude lower than that of TLD-100. The 355 K TL peak showed linear dose dependence only up to approximately 500 Gy and the 520 K peak up to approximately 1800 Gy.

Dose-Response Relationship, Radiation↗
PubMed2006

Non-monotonic dose dependence of thermoluminescence.

The thermoluminescence (TL) intensity in different materials is usually a monotonic increasing function of the dose, which quite often reaches a saturation value. In several materials, however, non-monotonic dose dependence has been observed. The TL intensity reached a maximum at a certain dose and decreased at higher ones. Some authors refer to this effect as 'radiation damage'. In the present work, we show that the non-monotonic dependence can easily be demonstrated to result from competition between transitions model with two trapping states and two kinds of recombination centres. Two kinds of competition are considered. One in which competition during excitation dominates, the filling of the active luminescence centre is non-monotonic, and the resulting TL is non-monotonic. In the other, the filling of traps and centres is monotonically increasing, but the competition during heating causes TL intensity to reach a maximum and decline at higher doses.

Algorithms↗
PubMed2006

Superlinear dose dependence of high temperature thermoluminescence peaks in Al2O3:C.

We report on strong superlinearity of high temperature (300-700 degrees C) thermoluminescence (TL) peaks in alpha-Al2O3:C powder. The main dosimetric peak at approximately 200 degrees C, previously found to exhibit slight superlinearity, is now shown to yield a slope of approximately 1.15 on a log(intensity) vs. log(dose) curve. Higher temperature peaks at approximately 320, 450 and 650 degrees C, previously reported following UV and X-ray excitation, have now been observed after beta irradiation and showed stronger superlinearity. Using a blue filter, the weak peak at approximately 320 degrees C started about quadratically and the slope on the log-log scale decreased gradually from 2 to about unity at approximately 100 Gy. The two higher temperature peaks at approximately 450 and approximately 650 degrees C also exhibited a strong superlinear dose dependence in this dose range, with an average slope of approximately 2. Roughly similar behaviour has been found when a UV filter was used. The possible explanation of the strong superlinearity is discussed.

Aluminum Oxide↗
PubMed2006

Multiwalled carbon nanotube supported PtRu for the anode of direct methanol fuel cells.

The activity of the methanol oxidation reaction of a multiwalled carbon nanotube (MWCNT)-supported PtRu catalyst was investigated and compared with the Vulcan XC-72 carbon-supported catalyst. The PtRu nanoparticles with 1:1 and 7:3 atomic ratios (with similar PtRu loadings and morphological structures) were deposited both on the MWCNTs and on the carbon. Cyclicvoltammetry results demonstrated that the MWCNT-supported PtRu catalyst exhibited a higher mass activity (mA mg(-1) of PtRu) for the methanol oxidation reaction than the carbon-supported PtRu under the condition that both catalysts possess more or less the same PtRu loadings, particle sizes, dispersions, and electrochemical surface area. The direct methanol fuel cell performance test data showed that MWCNT-supported PtRu catalysts yielded about 35-39% higher power densities than the carbon-supported PtRu.

Journal Article↗
PubMed2006

Effects of L-malate on physical stamina and activities of enzymes related to the malate-aspartate shuttle in liver of mice.

L-malate, a tricarboxylic acid cycle (TCA) intermediate, plays an important role in transporting NADH from cytosol to mitochondria for energy production and may be involved in the beneficial effects of improving physical stamina. In the present study, we investigated the effects of L-malate on the performance of forced swimming time and blood biochemical parameters related to fatigue - blood urea nitrogen (BUN), glucose (Glc), creatine kinase (CK),total protein (TP) and lactic acid (LA). To investigate the effects of L-malate on the malate-aspartate shuttle and energy metabolism in mice, the activities of enzymes related to the malate-aspartate shuttle were measured. L-malate was orally administered to mice continuously for 30 days using a feeding atraumatic needle. The swimming time was increased by 26.1 % and 28.5 %, respectively, in the 0.210 g/kg and 0.630 g/kg L-malate-treated group compared with the control group. There were no differences in the concentrations of Glc, BUN and TP between the L-malate-treated groups and the control groups. However, the levels of CK were significantly decreased in the L-malate-treated groups. The results predict a potential benefit of L-malate for improving physical stamina and minimizing muscle damage during swimming exercise. The activities of cytosolic and mitochondrial malate dehydrogenase were significantly elevated in the L-malate-treated group compared with the control group. These enzymatic activities may be useful indicators for evaluating changes affecting the malate-aspartate shuttle and energy metabolism in the liver of mice.

Administration, Oral↗
PubMed2006

Changes in motor cortex excitability with stimulation of anterior thalamus in epilepsy.

BACKGROUND: Deep brain stimulation (DBS) is an effective treatment for movement disorders and pain. Recently, bilateral DBS of the anterior nucleus of thalamus (AN) was performed for the treatment of intractable epilepsy. This surgery reduced seizure frequency in an initial group of patients. However, its physiologic effects on the cortex and mechanisms of action remain poorly understood. Different classes of antiepileptic drugs (AEDs) have distinct effects on the excitatory and inhibitory circuits in the motor cortex, which can be studied noninvasively by transcranial magnetic stimulation (TMS). OBJECTIVE: To examine the effects of bilateral AN DBS on motor cortex excitability in epilepsy and compare these to the known effects of AEDs. METHODS: Cortical excitability was assessed in five medicated epilepsy patients with bilateral stimulators implanted in the anterior thalamus and nine healthy controls. Single and paired TMS were used to examine cortical inhibitory and facilitatory circuits. Electromyography was recorded from the dominant hand, and TMS was applied over the contralateral motor cortex. Patients were studied during DBS turned off (OFF condition), DBS with cycling stimulation mode (1 minute on, 5 minutes off; CYCLE), and DBS with continuous stimulation (CONTINUOUS) in random order on 3 consecutive days. RESULTS: Motor thresholds were increased in the patients regardless of DBS condition. Active short-interval intracortical inhibition (SICI) was significantly reduced in the OFF and CYCLE conditions but returned toward normal levels in the CONTINUOUS condition. Rest SICI, long interval intracortical inhibition, and silent period duration were unchanged. CONCLUSIONS: Increased short-interval intracortical inhibition with continuous deep brain stimulation (DBS) suggests that thalamic DBS might drive cortical inhibitory circuits, similar to antiepileptic drugs that enhance gamma-aminobutyric acid inhibition.

Adult↗
PubMed2006

Cost-consequence analysis in a French setting of screening and optimal treatment of nephropathy in hypertensive patients with type 2 diabetes.

AIM: Forty percent of hypertensive type 2 diabetes patients develop nephropathy (microalbuminuria/overt nephropathy), indicating end organ damage, increased risk of cardiovascular disease (CVD), and death. In France, screening rates and nephropathy treatment are suboptimal. We assessed the health economic impact of nephropathy screening in hypertensive patients with type 2 diabetes followed by optimal antihypertensive/nephroprotective therapy in those who have nephropathy in France. METHODS: A Markov/Monte Carlo model simulated lifetime impacts of screening for albuminuria (microalbuminuria/overt nephropathy) using semi-quantitative urine dipsticks in a primary care setting, and subsequent addition of irbesartan 300 mg to conventional therapy in hypertensive type 2 diabetes patients identified as having nephropathy. Progression from no renal disease to end-stage renal disease (ESRD) was simulated. Probabilities, utilities and costs of CVD events, medications and ESRD treatment came from published sources. Cumulative incidence of ESRD, life expectancy, quality-adjusted life years (QALYs) and direct costs were projected. Second-order Monte Carlo simulation accounted for uncertainty in multiple parameters. Costs and QALYs were discounted at 3% annually. RESULTS: Screening and optimized treatment led to a 42% reduction in the cumulative incidence of ESRD from 10.1 +/- 9.9% without screening to 5.8 +/- 5.7%, improvements in life expectancy of 0.38 +/- 0.59 years, improvements of 0.29 +/- 0.32 QALYs, and decreased costs of Euro 4,812 +/- 7,882/patient over 25 years. Sensitivity analysis showed that the results were robust. Screening was most beneficial when performed in younger patients. CONCLUSION: In hypertensive patients with type 2 diabetes, screening for albuminuria followed by optimal antihypertensive/nephroprotective treatment improves patient outcomes and leads to cost savings in France.

Adult↗
PubMed2006

Upregulation of osteopontin gene expression in diabetic rat proximal tubular cells revealed by microarray profiling.

Progression of diabetic nephropathy appears directly related to renal tubulointerstitial injury, but the involved genes are incompletely delineated. To identify such genes, DNA microarray analysis was performed with RNA from renal proximal tubules (RPTs) of streptozotocin-induced diabetic Wistar rats, spontaneously diabetic BioBreeding rats, and rat immortalized renal proximal tubular cells (IRPTCs) exposed to high glucose (25 mM) medium for 2 weeks. Osteopontin (OPN) mRNA expression was quantified by real time-quantitative polymerase chain reaction (RT-qPCR) or conventional reverse transcriptase-polymerase chain reaction (RT-PCR). OPN mRNA expression was upregulated (5-70-fold increase) in diabetic rat RPTs and in IRPTCs chronically exposed to high glucose compared to control RPTs and IRPTCs. High glucose, angiotensin II, phorbol 12-myristate 13-acetate and transforming growth factor-beta 1 (TGF-beta1) stimulated OPN mRNA expression in IRPTCs in a dose- and time-dependent manner. This effect was inhibited by tiron, taurine, diphenylene iodinium, losartan, perindopril, calphostin C, or LY 379196 but not PD123319. IRPTCs overexpressing dominant-negative protein kinase C-beta 1 (PKC-beta1) cDNA or antisense TGF-beta1 cDNA prevented the high glucose effect on OPN mRNA expression. We concluded that high glucose-mediated increases in OPN gene expression in diabetic rat RPTs and IRPTCs are mediated, at least in part, via reactive oxygen species generation, intrarenal rennin-angiotensin system activation, TGF-beta1 expression, and PKC-beta1 signaling.

Angiotensin II↗
PubMed2006

Effect of over-expression of neuropathy target esterase on mammalian cell proliferation.

Neuropathy target esterase (NTE), the human homologue of a protein required for brain development in Drosophila, is expressed primarily in neural cells but is also detected in non-neural cells. Although NTE has been proposed to play a role in neurite outgrowth and process elongation during neurodifferentiation, the function of NTE has not been defined in neural cells. In this study we have investigated the possible role of NTE in neuroblastoma cells and non-neural cells using an over-expression strategy. Over-expression of NTE in human neuroblastoma SH-SY5Y cells and monkey kidney COS7 cells led to an accumulation of NTE on the cytoplasmic surface of the endoplasmic reticulum and inhibition of cell proliferation. In particular, high levels of NTE arrested COS7 cells at G2/M stage yet was not associated with arrest at a particular phase of the cell cycle in SH-SY5Y cells. Moreover, over-expression of NTE did not induce apoptosis in two kinds of cell lines as assessed by flow cytometry. These results suggest that the role of NTE over-expression in cell proliferation is associated with different mechanisms in different cells.

Animals↗
PubMed2006

Effects of a single nucleotide polymorphism on the expression of human tumor necrosis factor-alpha.

Tumor necrosis factor (TNF)-alpha plays a prominent role in inflammations and is a proinflammatory cytokine that has been implicated in the pathogenesis of autoimmune and infectious diseases. Recent association studies have found that the TNF-alpha-857T allele was associated with several disorders. Here we demonstrate, with reporter genes under the control of the two allelic TNF-alpha promoters, that the minor allele -857T is a much stronger transcriptional activator than the major allele -857C in RAW264.7 cell line in response to lipopolysaccharide stimulation. However, the result was not consistent in HeLa cell line. Furthermore, for the quantitative analysis of TNF-alpha synthesis between the -857C/C genotype from healthy subjects and the -857C/T genotype from AS patients, the quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay were performed separately. There was no significant difference between the two groups at the level of mRNA and protein. These results show that this polymorphism may have a direct effect on TNF-alpha regulation in a tissue-specific manner, and apart from the polymorphism at -857 in the TNF-alpha promoter, there may be other factors affecting the expression of TNF-alpha.

Adult↗