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Biomedical subjects

Hajime Nakamura

Publications and source records attributed to Hajime Nakamura.

At least 19 recordsLinked to original sources
PubMed2007

Contribution of thioredoxin reductase to T-cell mitogenesis and NF-kappaB DNA-binding promoted by selenite.

Although the essential role of selenium for cellular immune responses is obvious, delineation of the functions is lacking because selenium can either promote or inhibit cell growth, cytokine production, and activation of transcription factor nuclear factor-kappaB (NF-kappaB). Studies with human thioredoxin-1 (Trx-1)-transgenic (Tg) mice were conducted to evaluate the relationship between stimulation of T-cell mitogenic response by sodium selenite and the intracellular Trx-1 levels, and the activities of selenoenzymes and NF-kappaB-DNA binding. Concanavalin A-induced mitogenesis of wild-type mouse splenic cells was stimulated by exposure to low levels of selenite (0.02-0.1 microM), with augmentation of NF-kappaB-DNA binding activity. Treatment with NF-kappaB nuclear translocation inhibitor SN50 or thioredoxin reductase (TR) inhibitor aurothioglucose depressed this stimulatory action. The mitogenic response of Trx-1-Tg mouse splenic cells was enhanced by exposure to relatively high levels of selenite (> or = 0.05 microM), compared with the wild-type mouse. Selenite also augmented TR activity but not cellular glutathione peroxidase activity in the Trx-1-overexpressed cells. These results suggest that the stimulation of T-cell mitogenic response by the physiological levels of selenite is predominantly caused by increased TR activity, which may lead to reduction of Trx-1 dependent on the intracellular expression level and promotion of DNA binding of NF-kappaB.

Animals↗
PubMed2006

Correlation between middle-ear pressure-regulation functions and outcome of type-I tympanoplasty.

OBJECTIVES: To examine the correlation between the middle-ear pressure-regulation functions including active eustachian tube (ET) functions and transmucosal gas exchange function, and outcome of tympanoplasty. PATIENTS AND METHODS: Seventy five patients (78 ears) with non-cholesteatomatous chronic otitis media with eardrum perforation but without ossicular damage or middle-ear anomaly participated in this study. Before surgery, patency of the ET was examined by applying positive pressure to the middle ear through the eardrum perforation, and then the ET pressure-regulation functions were examined using the inflation-deflation test. Also their transmucosal gas exchange function was evaluated by examining the presence or absence of aeration in the mastoid on the CT before surgery or through the microscope during the surgery. All of them underwent type-I tympanoplasty, and their postoperative conditions including the hearing were followed for more than 6 months. The outcome of the surgery was judged as poor outcome when they had any of the following conditions; more than 20 dB of mean air-bone gap, spontaneous perforation within 6 months, or persistent wet condition including recurrent otorrhea. RESULTS: First, the outcome of all the four ears of which ETs were considered mechanically obstructed was poor. Next, among the remaining 74 ears, none of the three individual parameters, including positive and negative middle-ear pressure-equalizing functions and mastoid aeration, showed significantly positive correlation with the outcome of the surgery, but significantly higher incidence of poor outcome was seen only when all the three parameters were poor. CONCLUSIONS: These results indicated that impairment of all the middle-ear pressure-regulation functions was likely to cause poor outcome of tympanoplasty, and also allowed us reconfirm that ears with mechanically obstructed ETs were contraindicated for tympanoplasty. Therefore, assessment of mastoid condition is important as well as the ET function before tympanoplasty.

Adolescent↗
PubMed2006

Extracellular thioredoxin and thioredoxin-binding protein 2 in control of cancer.

Thioredoxin-1 (TRX) is a redox-active protein with multiple intracellular and extracellular functions. Intracellular redox balance is maintained by the TRX family and its related molecules. Extracellular TRX shows cytoprotective effects, while truncated Trx80 has more mitogenic activity. Exogenously administered TRX does not promote the growth of cancer in vivo and shows anti-chemotactic effect for neutrophils and anti-inflammatory functions. Thioredoxin is released from cells in response to oxidative stress and TRX levels in plasma or serum are good markers for oxidative stress associated with cancer. Thioredoxin-binding protein 2 (TBP-2) is an endogenous negative regulator of TRX and a tumor suppressor.

Carrier Proteins↗
PubMed2006

Thioredoxin-1 protects against hyperoxia-induced apoptosis in cells of the alveolar walls.

BACKGROUND: The mechanisms of hyperoxia-induced lung injury remain poorly defined. Thioredoxin-1 (TRX-1) is a small ubiquitous protein that acts as an important radical scavenger. We investigated the effect of TRX-1 on apoptosis in hyperoxia-induced lung injury. METHODS: Mice were exposed to 98% O(2) to produce a model of hyperoxia-induced lung injury. Using transgenic mice overexpressing human TRX-1 (hTRX-1), we assessed lung structure (n=4 per group), immunohistochemical staining for 8-hydroxy-deoxyguanosine (n=4 per group), TUNEL staining (n=5 per group), cytokine (n=5 per group) of IL-1beta and IL-6, and protein (n=6 per group) and m-RNA levels (n=4 per group) (or both) of cytochrome c, Bcl-2, Bax, p21, and p53 in the lungs. RESULTS: After exposure to hyperoxia, hTRX-1 transgenic mice had significantly decreased alveolar damage. The apoptotic index was significantly lower in hTRX-1 transgenic mice than in wild-type (WT) mice after exposure to hyperoxia. Protein expression of cytochrome c in the lung was significantly lower in hTRX-1 transgenic mice than in WT mice after exposure to hyperoxia. Protein expression and m-RNA levels of Bcl-2 in the lung were significantly higher in hTRX-1 transgenic mice than in WT mice after exposure to hyperoxia. TRX-1 had no effect on the protein and m-RNA levels of Bax and p21. The protein and m-RNA levels of p53 was unaffected by hyperoxia in hTRX-1 transgenic mice. The cytokine level of IL-6 was significantly higher in hTRX-1 transgenic mice than in WT mice after exposure to hyperoxia. TRX-1 had no effect on cytokine level of IL-1beta. CONCLUSIONS: These findings suggest that overexpression of hTRX-1 protects against hyperoxia-induced apoptosis in cells of the alveolar walls. The up-regulating Bcl-2 protein is considered to be one of antiapoptotic effects of TRX-1 in hyperoxia-induced lung injury.

Animals↗
PubMed2006

Human thioredoxin-1 ameliorates experimental murine colitis in association with suppressed macrophage inhibitory factor production.

BACKGROUND & AIMS: Thioredoxin-1 (TRX) is a small multifunctional protein with antioxidative and redox-regulating functions. In this study, we investigated the significance of TRX in patients with inflammatory bowel disease (IBD) and the ability and mechanism to ameliorate experimental colitis. METHODS: Serum TRX and macrophage migration inhibitory factor (MIF) levels were measured in patients with IBD. The effects of TRX were evaluated in a dextran sulfate sodium (DSS)-induced colitis model by comparing TRX-overexpressing transgenic (TRX-TG) and control mice. We further evaluated the effect of recombinant human TRX (rhTRX) administration on DSS-induced colitis and colonic inflammation of interleukin (IL)-10 knockout (IL-10 KO) mice. Colonic inflammation was examined clinically and histologically. Proinflammatory cytokine levels were examined in colonic tissues, and MIF levels were measured in colonic tissues and sera in mice. The effect of TRX on MIF production was also analyzed in vitro. RESULTS: Serum TRX and MIF levels were significantly higher in patients with IBD than normal controls, and TRX levels correlated with disease activity. TRX significantly ameliorated DSS-induced colitis and colonic inflammation of IL-10 KO mice. Increase of tumor necrosis factor-alpha and interferon-gamma in colonic tissues was significantly suppressed in TRX-TG mice compared with wild-type mice. MIF levels in colonic tissues and sera were significantly lower in TRX-TG mice than in wild-type mice, irrespective of DSS administration. Anti-TRX treatment exacerbated DSS-induced colitis. In vitro studies demonstrated that rhTRX suppressed MIF production in human monocyte cells. CONCLUSIONS: TRX might have a potential as a novel therapeutic agent for the treatment of IBD.

Animals↗
PubMed2006

Recombinant human thioredoxin suppresses lipopolysaccharide-induced bronchoalveolar neutrophil infiltration in rat.

Human thioredoxin (TRX) is a multifunctional redox-active protein. We previously reported that the intraperitoneal administration of recombinant human thioredoxin (rhTRX) attenuates inflammatory cytokine- or bleomycin-induced lung injury in mice. In this study, the effect of rhTRX injected intravenously after lipopolysaccharide (LPS) injection was analyzed in rats. Rats were injected with LPS followed by treatment with rhTRX. Although the bolus injection exerted no protective effect, continuous intravenous administration of rhTRX significantly suppressed percentage number of neutrophils in bronchoalveolar lavage fluid. Histological examination also showed that rhTRX decreased neutrophil infiltration in the lung tissues. Administered rhTRX was mainly excreted into the urine and the tissue accumulation of rhTRX in the lung was marginal. LPS-induced oxidative stress in the lung was slight in this model. These results demonstrated that continuous intravenous administration of rhTRX suppresses LPS-induced bronchoalveolar neutrophil infiltration by an anti-chemotactic effect. Administration of rhTRX did not promote the tumor growth nor affect chemosensitivity in the xenotransplantation model, suggesting the safety of rhTRX therapy for cancer patients.

Animals↗
PubMed2006

Evaluation of mutation effects on UGT1A1 activity toward 17beta-estradiol using liquid chromatography-tandem mass spectrometry.

Mutations in the gene encoding UDP-glucuronosyltransferase 1A1 (UGT1A1) may reduce the glucuronidation of estradiol, bilirubin, etc. In the present study, we used a liquid chromatography-tandem mass spectrometry (LC/MS/MS) method to assay the activities of recombinant mutated UGT1A1 toward 17beta-estradiol (E2), by determining its glucuronide (E2G) content. Direct evidence for glucuronide formation was provided by E2G-specific ion peaks. The UGT1A1 activities of G71R (exon 1), F83L (exon 1), I322V (exon 2) and G493R (exon 5) mutants were 24, 30, 18 and 0.6% of the normal UGT1A1 activity, respectively. In conclusion, our study showed that LC/MS/MS enabled accurate evaluation of the effects of mutations on recombinant UGT1A1 activity towards E2.

Animals↗
PubMed2006

Thioredoxin protects against joint destruction in a murine arthritis model.

Thioredoxin (TRX) is an oxidative stress-inducible biological antioxidant that is highly expressed in the synoviocytes of rheumatoid arthritis (RA) patients. There is much evidence that oxidative stress plays a key role in the inflammation and destruction of RA joints; the functional relationship between TRX and RA remains unknown, however. We therefore investigated the role played by TRX in the inflammatory and joint-damaging processes of RA using a murine model in which arthritis was induced by administering a mixture of anti-type II collagen monoclonal antibodies (mAb) and lipopolysaccharide (LPS). In Wt mice mAb/LPS injection induced neutrophil infiltration, cartilage destruction, and chondrocyte apoptosis within the joints, all of which were dramatically suppressed in TRX transgenic (TRX-Tg) mice. Moreover, the 8-hydoxy-2'-deoxyguanosine (8-OHdG) expression seen in Wt mice after mAb/LPS injection was almost completely inhibited in TRX-Tg mice. The administration of recombinant TRX also suppressed mAb/LPS-induced joint swelling in Wt mice. Taken together, these results suggest that TRX protects against arthritis and is a plausible candidate with which to develop novel therapies for the treatment of RA.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2006

Control of mitochondrial outer membrane permeabilization and Bcl-xL levels by thioredoxin 2 in DT40 cells.

Mitochondria play a central role in the initiation of apoptosis, which is regulated by various factors such as ATP synthesis, reactive oxygen species, redox status, and outer membrane permeabilization. Disruption of chicken thioredoxin 2 (Trx2), a mitochondrial redox-regulating protein, results in apoptosis in DT40 cells. To investigate the mechanism of this apoptosis, we prepared transfectants expressing control (DT40-TRX2-/-), human thioredoxin 2 (TRX2) (DT40-hTRX2), or redox-inactive TRX2 (DT40-hTRX2CS) in conditional Trx2-deficient DT40 cells containing a tetracycline-repressible Trx2 gene. Production of ATP was not significantly changed by down-regulation of Trx2 expression. The generation of reactive oxygen species was enhanced by the down-regulation of Trx2 expression in DT40-TRX2-/-. Unexpectedly, the change was blocked in both DT40-hTRX2 and DT40-hTRX2CS cells. The down-regulation of Trx2 expression caused the release of cytochrome c and apoptosis-inducing factor on day 3, and apoptosis on day 5. These changes were also suppressed in both DT40-hTRX2 and DT40-hTRX2CS cells, suggesting that TRX2 regulates mitochondrial outer membrane permeabilization and apoptosis by redox-active site cysteine-independent mechanisms. The down-regulation of Trx2 expression caused a decrease in the protein level of Bcl-xL on day 3, whereas the protein level of Bcl-2 did not change until day 4, and the mRNA level of Bcl-xL was unchanged. The decrease in Bcl-xL was not blocked by a caspase 3 inhibitor but blocked in both DT40-hTRX2 and DT40-hTRX2CS. These findings indicate a link between the redox active site cysteine-independent action of TRX2 and the level of Bcl-xL in the regulation of apoptosis.

Adenosine Triphosphate↗
PubMed2006

Thioredoxin-binding protein-2 (TBP-2): its potential roles in the aging process.

Thioredoxin (TRX) binding protein-2 (TBP-2), a negative regulator of TRX, is involved in intracellular redox regulation and cellular growth. The expression of TBP-2 is frequently lost in tumor cell lines and tissues, whereas the ectopic expression of TBP-2 suppresses cellular proliferation along with cell cycle arrest at the G1 phase. TBP-2 was also reported to be a cellular senescence-associated gene. Besides the retardation of cellular growth, the reduction of white adipose, and alteration of the energy pathway are involved in several features of the aging process. We have generated TBP-2 genetically modified mice and found that TBP-2 is closely linked to lipid metabolism. Indeed, TBP-2 has been suggesting to be related to familial combined hyperlipidemia analyzed by a spontaneous mutant mouse strain. As lipid metabolism is one of the most primitive sources of energy production, we discussed the possible roles of TBP-2 in the regulation of energy utilization connected to the aging process.

Animals↗
PubMed2006

Efficacy of ultrasound-assisted stress testing using a hand-carried ultrasound device for diagnosis of coronary artery disease.

BACKGROUND: Exercise echocardiography is an effective means of noninvasively detecting coronary artery disease (CAD), and hand-carried cardiac ultrasound (HCU) devices are now being used to diagnose CAD in emergency rooms and at bedsides. OBJECTIVE: To compare the efficacies of exercise echocardiography with an HCU device (EchoCG-HCU) and exercise electrocardiography (ECG) in the diagnosis of CAD. METHODS: Fifty-eight patients underwent symptom-limited treadmill exercise testing. Two-dimensional echocardiographic images were obtained from standard parasternal and apical windows at rest and immediately after exercise using an HCU device (180 PLUS SonoSite Inc, Bothell, Wash). Wall motion was scored for each of 16 left ventricular segments using a 5-point grading system. The development of new or worsening wall motion was considered to be indicative of ischemia. RESULTS: When identifying CAD using exercise ECG, the sensitivity ws 63%, the specificity was 72%, and the diagnostic accuracy was 69%. By comparison, with exercise EchoCG-HCU the sensitivity was 68%, the specificity was 90%, and the diagnostic accuracy was 83%. Moreover, the specificity of exercise EchoCG-HCU was significantly higher than that of exercise ECG (p < .05). CONCLUSION: Exercise EchoCG-HCU is at least as useful as exercise ECG for diagnosing CAD.

Coronary Artery Disease↗
PubMed2006

Redox regulation of mast cell histamine release in thioredoxin-1 (TRX) transgenic mice.

Thioredoxin-1 (TRX) is a stress-inducible redox-regulatory protein with antioxidative and anti-inflammatory effects. Here we show that the release of histamine from mast cells elicited by cross-linking of high-affinity receptor for IgE (FcepsilonRI) was significantly suppressed in TRX transgenic (TRX-tg) mice compared to wild type (WT) mice. Intracellular reactive oxygen species (ROS) of mast cells stimulated by IgE and antigen was also reduced in TRX-tg mice compared to WT mice. Whereas there was no difference in the production of cytokines (IL-6 and TNF-alpha) from mast cells in response to 2,4-dinitrophenylated bovine serum albumin (DNP-BSA) stimulation in TRX-tg and WT mice. Immunological status of TRX-tg mice inclined to T helper (Th) 2 dominant in primary immune response, although there was no difference in the population of dendritic cells (DCs) and regulatory T cells. We conclude that the histamine release from mast cells in TRX-tg mice is suppressed by inhibition of ROS generation. As ROS are involved in mast cell activation and facilitate mediator release, TRX may be a key signaling molecule regulating the early events in the IgE signaling in mast cells and the allergic inflammation.

Animals↗
PubMed2006

Clinical significance of serum thioredoxin 1 levels in patients with acute pancreatitis.

OBJECTIVE: Thioredoxin 1 (TRX-1), a redox-regulating protein with antioxidant activity, is induced by oxidative stress, and serum TRX-1 levels are recognized as an oxidative-stress marker. The aim of this study was to clarify the clinical significance of serum TRX-1 levels in patients with acute pancreatitis (AP) and evaluate the usefulness of this measurement in assessing disease severity. METHODS: Serum TRX-1 levels were determined on admission in 18 patients with severe AP and 36 patients with mild AP. We also investigated the relationship between serum TRX-1 levels and clinical and laboratory data. RESULTS: The median serum TRX-1 levels on admission were 54.9 ng/mL in mild AP and 118.8 ng/mL in severe AP. When the cutoff value for TRX-1 in predicting severe AP was determined to be 100 ng/mL, its sensitivity, specificity, and accuracy were 83.3%, 94.4%, and 90.7%, respectively. A significant correlation was observed between serum TRX-1 levels and Ranson score (r = 0.674), C-reactive protein (r = 0.718), interleukin 6 (r = 0.712), leukocyte count (r = 0.642), and serum amylase (r = 0.436). CONCLUSIONS: Serum TRX-1 levels significantly correlate with AP severity. TRX-1 should constitute a reliable oxidative-stress marker for the evaluation of AP severity in relation to oxidative stress.

Acute Disease↗
PubMed2006

Thioredoxin inhibits NMDA-induced neurotoxicity in the rat retina.

Thioredoxin (TRX) plays a variety of redox-related roles in organisms. To investigate its function as an endogenous redox regulator in NMDA-induced retinal neurotoxicity, we injected NMDA with TRX, mutant TRX or saline into the vitreous cavity of rat eyes. Retinal ganglion cells were rescued by TRX, compared with saline, when evaluated by retrograde labeling analysis at 7 days after NMDA injection. TRX, but not its mutant form, prevented NMDA-induced apoptosis in the retina, as measured by terminal deoxynucleotidyl transferase-mediated UTP nick-end labeling. The induction of caspase 3 and 9, but not caspase 8, by NMDA was significantly lower in TRX-treated eyes than in saline-treated eyes. NMDA-induced activation of the MAPKs, p38 kinase and c-Jun N-terminal kinase after 6 h and of the MAPK kinases (MKKs) MKK3/6 and MKK4 after 3 h was markedly suppressed in retinal ganglion cells by TRX but not by the mutant form. NMDA-induced increases in protein carbonylation, nitrosylation and lipid peroxidation were also suppressed in TRX-treated eyes. We concluded that the intravitreous injection of TRX effectively attenuated NMDA-induced retinal cell damage and that suppression of oxidative stress and inhibition of apoptotic signaling pathways were involved in this neuroprotection.

Animals↗
PubMed2006

In vivo and in vitro feasibility studies of intraocular use of seprafilm to close retinal breaks in bovine and rabbit eyes.

PURPOSE: Seprafilm, a sodium hyaluronate/carboxymethylcellulose absorbable barrier developed to prevent adhesions after abdominal surgery, adheres well to wet tissue. The authors studied the efficacy of this film for sealing retinal breaks in animals. METHODS: In an in vitro study, a retinal detachment with a hole was created in bovine eyecups after the vitreous gel was removed. Seprafilm was placed over the retinal hole, and the strength of the retinal adhesion was measured by pulling the film. Permeability was tested by applying methylene blue to the film covering the retinal break. Seprafilm also was soaked in balanced salt solution (BSS) incubated at 37 degrees C, and the pH of the BSS containing Seprafilm was measured as it melted. In an in vivo study, Seprafilm was powdered and mixed in BSS solution, and 0.1 mL was injected into the right vitreous cavity in study rabbits. The same amount of BSS was injected into the right vitreous cavity in control rabbits. Ophthalmologic examinations were performed. Bilateral electroretinograms were recorded simultaneously before and 6 weeks after injection. Both eyes were enucleated for histologic evaluation. RESULTS: Seprafilm adhered well to the retina, was impermeable to methylene blue, and remained solid in BSS for 30 days before it dissolved, and its pH ranged from 7.2 to 8.0. No intraocular inflammatory reaction occurred after intravitreous injection of Seprafilm solution. There was no significant difference in amplitudes or implicit times of electroretinogram a-waves, b-waves, and oscillatory potentials before and after injection and between study and control groups. No significant retinal abnormality was detected by light microscopy in either group. CONCLUSIONS: The film adhered well to the retina with no signs of ocular toxicities. Further study is warranted for possible means of patching retinal breaks.

Animals↗
PubMed2005

Protective roles of redox-active protein thioredoxin-1 for severe acute pancreatitis.

Severe acute pancreatitis is a disease with high mortality, and infiltration of inflammatory cells and reactive oxygen species have a crucial role in the pathophysiology of this disease. Thioredoxin-1 (TRX-1) is an endogenous redox-active multifunctional protein with antioxidant and anti-inflammatory effects. TRX-1 is induced in various inflammatory conditions and shows cytoprotective effects. The aim of the present study was to clarify the protective roles of TRX-1 in the host defense mechanism against severe acute pancreatitis. Experimental acute pancreatitis was induced by intraperitoneal administration of cerulein, a CCK analog, and aggravated by lipopolysaccharide injection in transgenic mice overexpressing human TRX-1 (hTRX-1) and control C57BL/6 mice. Transgenic overexpression of hTRX-1 strikingly attenuated the severity of experimental acute pancreatitis. TRX-1 overexpression suppressed neutrophil infiltration as determined by myeloperoxidase activity, oxidative stress as determined by malondialdehyde concentration, and cytoplasmic degradation of inhibitor of kappaB-alpha, thereby suppressing proinflammatory cytokines, tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6; a neutrophil chemoattractant, keratinocyte-derived chemokine; and inducible nitric oxide synthase in the pancreas. Administration of recombinant hTRX-1 also suppressed neutrophil infiltration, reduced the inflammation of the pancreas and the lung, and improved the mortality rate. The present study suggests that TRX-1 has potent antioxidant and anti-inflammatory actions in experimental acute pancreatitis and might be a new therapeutic strategy to improve the prognosis of severe acute pancreatitis.

Acute Disease↗
PubMed2005

High thioredoxin expression is associated with resistance to docetaxel in primary breast cancer.

PURPOSE: Thioredoxin overexpression is suggested to be associated with resistance to several chemotherapeutic agents in vitro. In the present study, it has been studied whether or not high thioredoxin expression is associated with resistance to docetaxel therapy in breast cancer patients. PATIENTS AND METHODS: Sixty-three primary breast cancer patients were treated with docetaxel (60 mg/m(2), q3w) for four cycles in the neoadjuvant setting. Expression of thioredoxin, estrogen receptor (ER), p53, BRCA-1, and Bcl-2 in tumor tissues obtained before docetaxel therapy was studied by immunohistochemistry (thioredoxin, p53, BRCA-1, and Bcl-2) and enzyme immunoassay (ER), and relationship of expression of these biomarkers with a pathologic response was investigated. RESULTS: There was no significant correlation between the expression of p53, BRCA-1, or Bcl-2 and a response to docetaxel. However, tumors with high thioredoxin expression showed a significantly lower response rate (0%) than those with low thioredoxin expression (30.6%; P = 0.018) and ER-negative tumors showed a significantly higher response rate (32.4%) than ER-positive tumors (10.7%; P = 0.043). Thioredoxin expression significantly increased after docetaxel therapy (mean, 56.1%) as compared with that before docetaxel therapy (mean, 28.6%; P < 0.0001) but there was no significant association between the extent of increase in thioredoxin expression and response. CONCLUSION: High thioredoxin expression in prechemotherapy tumor samples, but not the increase in thioredoxin expression induced by docetaxel, is associated with resistance to docetaxel in breast cancer. Thioredoxin and ER might be clinically useful in the prediction of a response to docetaxel.

Antineoplastic Agents, Phytogenic↗