Ibrutinib and venetoclax as primary therapy in symptomatic, treatment-naïve Waldenström macroglobulinemia.

ABSTRACT: Concurrent Bruton tyrosine kinase and BCL2 inhibition has not yet been investigated in Waldenström macroglobulinemia (WM). We performed an investigator-initiated trial of ibrutinib and venetoclax in symptomatic treatment-naïve patients with MYD88-mutated WM. Patients received ibrutinib 420 mg once daily (cycle 1), followed by a ramp-up of venetoclax to 400 mg daily (cycle 2). The combination was then administered for 22 additional 4-week cycles. The attainment of very good partial response (VGPR) was the primary end point. Forty-five patients were enrolled in this study. The median baseline characteristics were as follows: age 67 years, serum IgM 43 g/L, and hemoglobin 102 g/L. Seventeen patients (38%) carried CXCR4 mutations. Nineteen patients (42%) achieved VGPR. Grade 3 or higher adverse events included neutropenia (38%), mucositis (9%), and tumor lysis syndrome (7%). Atrial fibrillation occurred in 3 (9%), and ventricular arrhythmia in 4 (9%) patients that included 2 grade 5 events. With a median follow-up of 24.4 months, the 24-month progression-free survival (PFS) and overall survival (OS) rates were 76% and 96%, respectively, and were not impacted by CXCR4 mutations. The median time on therapy was 10.2 months, and the median time after the end of therapy (EOT) was 13.3 months. Eleven of the 12 progression events occurred after EOT, and the 12-month PFS rates after EOT were 79%; 93% if VGPR was attained, and 69% for other patients (P = .12). Ibrutinib and venetoclax induced high VGPR rates and durable responses after EOT, although they were associated with a higher-than-expected rate of ventricular arrhythmia in patients with WM, leading to early study treatment termination. This trial was registered at www.clinicaltrials.gov as #NCT04273139.

Transcriptome Characterization of Short Distance Transport Stress in Beef Cattle Blood.

The transportation is a crucial phase in beef cattle industry, and the annual losses caused by beef cattle transport stress are substantial. Several studies have described the effect of long distance transportation stress on animal health, such as disorder in nervous, endocrine, immune, and metabolic system. However, molecular mechanisms underlying short distance transportation stress is still poorly understood. Present study aims to investigate the effect of short distance transportation by measuring the hematological indices and transcriptomic analysis. In this study, a total 10 Qinchuan cattle were used to compare the molecular characteristics of blood before and after transportation. We have found that a stress-related marker "white blood cell count (WBC)" increased significantly after transportation. The decrease in triglyceride (TG), cholestenone (CHO), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) showed that energy expenditure was increased after transportation, but not enough to activate fatty decomposition. Intriguingly, the decrease of malondialdehyde (MDA) showed that cattle were more resilience to oxidative stress. The RNA-seq showed that 1,092 differentially expressed genes (DEGs) were found (329 up-regulated and 763 down-regulated) between group before and group after. The GO and KEGG enrichment showed that the metabolic pathway and B cell function related pathways were enriched. Furthermore, median absolute deviation (MAD) top 5,000 genes were used to construct a co-expression network by weighted correlation network analysis (WGCNA), and 11 independent modules were identified. Combing with protein-protein interaction (PPI) analysis, the verification of quantitative real-time PCR (qPCR) and the correlation of B cell function, structural maintenance of chromosomes 3 (SMC3), jun proto-oncogene (JUN), and C-X-C motif chemokine ligand 10 (CXCL10) were suggested as potential molecular markers in identification of short distance transportation. Collectively, the blood RNA-seq analysis and WGCNA indicated that the disorder of B cell differentiation, proliferation, survival, and apoptosis were the potential molecular mechanism in short distance transportation stress. In conclusion, our results provide the novel insight about potential biomarkers for short distance transportation stress, which may serve as for diagnosing and preventing this condition in beef industry.

Subcapsular Injection of Ultrasonic Contrast Agent Distinguishes between Benign and Malignant Lymph Node Lesions Exhibiting Homogeneous Enhancement in Intravenous Contrast-Enhanced Ultrasound Images.

We aimed to evaluate whether subcapsular injection of ultrasonic contrast agent (UCA) can distinguish between benign and malignant lymph node (LN) lesions exhibiting homogeneous enhancement in intravenous contrast-enhanced ultrasound (CEUS) images. From November 2012 to July 2015, 32 patients with superficial lymphadenopathy exhibiting homogeneous enhancement after intravenous CEUS were enrolled. A small amount of UCA was injected into LNs using a subcapsular approach, and perfusion characteristics were recorded. Using the pathology identified via core needle biopsy as the gold standard, we calculated the sensitivity, specificity and accuracy of the technique in terms of distinguishing between benign and malignant LN lesions. Pathology revealed 23 cases of true benign and 9 cases of true malignant LN lesions; the former included 2 cases of tuberculosis and 21 cases of reactive hyperplasia, and the latter included 7 lymphomas and 2 metastases. Subcapsular CEUS diagnosed 24 benign and 8 malignant LN lesions. Most lymphomas (6 of 7, 85.7%) exhibited heterogeneous perfusion, with lymphatic tract distortion in the absence of interruption. Reactive hyperplasia LNs manifested as diffuse homogeneous or brush-like perfusion from the subcapsular region to the center, without lymphatic tract distortion. Metastatic LNs had lymphatic tract interruptions. The sensitivity, specificity, consistency and positive and negative predictive values were 77.8%, 95.6%, 90.6%, 87.5% and 91.7%, respectively. For LNs exhibiting uniform enhancement in intravenous CEUS imaging, subcapsular CEUS may help to distinguish between benign and malignant lesions. In particular, lymphatic distortion without interruption may specifically indicate a lymphoma.

Experimental and Preliminary Clinical Study of Real-Time Registration in Liver Tumors During Respiratory Motion Based on a Multimodality Image Navigation System.

PURPOSE: To develop a fusion imaging system that combines ultrasound and computed tomography for real-time tumor tracking and to validate the accuracy of performing registration via this approach during a specific breathing phase. MATERIALS AND METHODS: The initial part of the experimental study was performed using iodized oil injection in pig livers and was focused on determining the accuracy of registration. Eight points (A1-4 and B1-4) at different positions and with different target sizes were selected as target points. During respiratory motion, we used our self-designed system to perform the procedure either with (experimental group, E) or without (control group, C) the respiratory monitoring module. The registration errors were then compared between the 2 groups and within group E. The second part of this study was designed as a preliminary clinical study and was performed in 18 patients. Screening was performed to determine the combination of points on the body surface that provided the highest sensitivity to respiratory motion. Registration was performed either with (group E) or without (group C) the respiratory monitoring module. Registration errors were compared between the 2 groups. RESULTS: In part 1 of this study, there were fewer registration errors at each point in group E than at the corresponding points in group C (P < .01). In group E, there were more registration errors at points A1 and B1 than at the other points (P < .05). There was no significant difference in registration errors among the remaining points. During part 2 of the study, there was a significant difference in the registration errors between the 2 groups (P < .01). CONCLUSIONS: Real-time fusion registration is feasible and can be accurately performed during respiratory motions when using this system.

Soil nitrogen determines greenhouse gas emissions from northern peatlands under concurrent warming and vegetation shifting.

Boreal peatlands store an enormous pool of soil carbon that is dependent upon - and vulnerable to changes in - climate, as well as plant community composition. However, how nutrient availability affects the effects of climate and vegetation change on ecosystem processes in these nutrient-poor ecosystems remains unclear. Here we show that although warming promoted higher CH4 emissions, the concurrent addition of N counteracted most (79%) of this effect. The regulation effects of the vegetation functional group, associated with the substrate quality, suggest that CH4 emissions from peatlands under future warming will be less than expected with predicted shrub expansion. In contrast, N2O flux will be enhanced under future warming with predicted shrub expansion. Our study suggests that changes in greenhouse gas emissions in response to future warming and shifts in plant community composition depend on N availability, which reveals the complex interactions that occur when N is not a limiting nutrient.

Diabetes mellitus may worsen the prognosis in hepatocellular carcinoma patients undergoing curative microwave ablation.

PURPOSE: This study aimed to investigate the outcomes of hepatocellular carcinoma (HCC) patients after curative microwave ablation (MWA) with and without diabetes mellitus (DM). METHODS: A total of 308 patients with HCC were retrospectively studied from 2005 to 2012 over an 8-year period. They were all successfully treated by MWA. Progression-free survival (PFS) and overall survival (OS) were analyzed according to the status of DM. The presence of other comorbidities and tumor status were studied using multivariate analysis. RESULTS: Significant differences were observed both for 1-, 3-, 5- year's PFS rates (DM: 63.8, 23.0 and 15.8 vs non-DM: 72.7, 43.6 and 30.8%; p=0.013) and OS rates (DM: 87.3, 75.1 and 49.5% vs non-DM: 97.9, 82.9 and 70.5%; p=0.045) between patients with and without DM. Cox multivariate analysis identified the following factors significantly associated with PFS: (hazard ration (HR): 1.191, 95% CI: 1.051-1,349, p=0.006), AFP (HR:1.000, 95% CI: 1.000-1.000, p=0.022), alcohol abuse (>100g/d vs ≤100g/d, HR:1.579, 95% CI:1.128- 2.212, p=0.008), mean fasting plasma glucose level after initial therapy for HCC(>7.0 / ≤7.0, HR:2.728, 95%CI:1.414- 5.265, p=0.003); and the followings associated with OS:Child-Pugh classification A against B, C (risk 1.692, 95%CI 1.065-2.689, P=0.026), tumor diameter (risk 1.251. 95% CI 1.021-1.534, P=0.031), and AFP (risk 1.000. 95% CI 1.000- 1.000, P=0.000). CONCLUSION: DM may affect the HCC progression and overall survival in patients undergoing curative MWA. A good control of the glucose levels after ablation may be important for improving the prognosis of HCC.

γδ T cells control humoral immune response by inducing T follicular helper cell differentiation.

γδ T cells have many known functions, including the regulation of antibody responses. However, how γδ T cells control humoral immunity remains elusive. Here we show that complete Freund's adjuvant (CFA), but not alum, immunization induces a subpopulation of CXCR5-expressing γδ T cells in the draining lymph nodes. TCRγδ+CXCR5+ cells present antigens to, and induce CXCR5 on, CD4 T cells by releasing Wnt ligands to initiate the T follicular helper (Tfh) cell program. Accordingly, TCRδ-/- mice have impaired germinal center formation, inefficient Tfh cell differentiation, and reduced serum levels of chicken ovalbumin (OVA)-specific antibodies after CFA/OVA immunization. In a mouse model of lupus, TCRδ-/- mice develop milder glomerulonephritis, consistent with decreased serum levels of lupus-related autoantibodies, when compared with wild type mice. Thus, modulation of the γδ T cell-dependent humoral immune response may provide a novel therapy approach for the treatment of antibody-mediated autoimmunity.

Deficiency of Neuronal p38α MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1.

Amyloid ß (Aß) damages neurons and triggers microglial inflammatory activation in the Alzheimer disease (AD) brain. BACE1 is the primary enzyme in Aß generation. Neuroinflammation potentially up-regulates BACE1 expression and increases Aß production. In Alzheimer amyloid precursor protein-transgenic mice and SH-SY5Y cell models, we specifically knocked out or knocked down gene expression of mapk14, which encodes p38α MAPK, a kinase sensitive to inflammatory and oxidative stimuli. Using immunological and biochemical methods, we observed that reduction of p38α MAPK expression facilitated the lysosomal degradation of BACE1, decreased BACE1 protein and activity, and subsequently attenuated Aß generation in the AD mouse brain. Inhibition of p38α MAPK also enhanced autophagy. Blocking autophagy by treating cells with 3-methyladenine or overexpressing dominant-negative ATG5 abolished the deficiency of the p38α MAPK-induced BACE1 protein reduction in cultured cells. Thus, our study demonstrates that p38α MAPK plays a critical role in the regulation of BACE1 degradation and Aß generation in AD pathogenesis.

Identification and characterization of latency-associated peptide-expressing γδ T cells.

γδ T cells are a subset of lymphocytes specialized in protecting the host against pathogens and tumours. Here we describe a subset of regulatory γδ T cells that express the latency-associated peptide (LAP), a membrane-bound TGF-ß1. Thymic CD27+IFN-γ+CCR9+α4ß7+TCRγδ+ cells migrate to the periphery, particularly to Peyer's patches and small intestine lamina propria, where they upregulate LAP, downregulate IFN-γ via ATF-3 expression and acquire a regulatory phenotype. TCRγδ+LAP+ cells express antigen presentation molecules and function as antigen presenting cells that induce CD4+Foxp3+ regulatory T cells, although TCRγδ+LAP+ cells do not themselves express Foxp3. Identification of TCRγδ+LAP+ regulatory cells provides an avenue for understanding immune regulation and biologic processes linked to intestinal function and disease.

Graphene Oxide Based Nanocarrier Combined with a pH-Sensitive Tracer: A Vehicle for Concurrent pH Sensing and pH-Responsive Oligonucleotide Delivery.

We chemically tuned the oxidation status of graphene oxide (GO) and constructed a GO-based nanoplatform combined with a pH-sensitive fluorescence tracer that is designed for both pH sensing and pH-responsive drug delivery. A series of GOs oxidized to distinct degrees were examined to optimize the adsorption of the model drug, poly dT30. We determined that highly oxidized GO was a superior drug-carrier candidate in vitro when compared to GOs oxidized to lesser degrees. In the cell experiment, the synthesized pH-sensitive rhodamine dye was first applied to monitor cellular pH; under acidic conditions, protonated rhodamine fluoresces at 588 nm (λex=561 nm). When the dT30-GO nanocarrier was introduced into cells, a rhodamine-triggered competition reaction occurred, and this led to the release of the oligonucleotides and the quenching of rhodamine fluorescence by GO. Our results indicate high drug loading (FAM-dT30/GO=25/50 µg/mL) and rapid cellular uptake (<0.5 h) of the nanocarrier which can potentially be used for targeted RNAi delivery to the acidic milieu of tumors.

A fluorescence turn-on probe for cysteine and homocysteine based on thiol-triggered benzothiazolidine ring formation.

We synthesized a new coumarin-based probe TP, containing a disulfide moiety, to detect biothiols in cells. A fluorescence turn-on response is induced by the thiol-disulfide exchange of the probe, with subsequent intramolecular benzothiazolidine ring formation giving rise to a fluorescent product. The probe exhibits an excellent selectivity for cysteine (Cys) and homocysteine (Hcy) over glutathione (GSH) and other amino acids. The fluorescent probe also exhibits a highly sensitive fluorescence turn-on response to Cys and Hcy with detection limits of 0.8 µM for Cys and 0.5 µM for Hcy. In addition, confocal fluorescence microscopy imaging using RAW264.7 macrophages demonstrates that the probe TP could be an efficient fluorescent detector for thiols in living cells.

Preoperative neutrophil-to-lymphocyte ratio is a predictor of recurrence following thermal ablation for recurrent hepatocellular carcinoma: a retrospective analysis.

PURPOSE: The aim of this study is to determine the predictive value of preoperative blood neutrophil-to-lymphocyte ratio (NLR) for recurrence in recurrent hepatocellular carcinoma (RHCC) patients following thermal ablation. MATERIAL AND METHODS: This retrospective study enrolled 506 RHCC patients who underwent thermal ablation from April 2006 to April 2014. The clinicopathological parameters including NLR were evaluated to identify predictors of recurrence rate after thermal ablation. A Cox multiple regression analysis was performed to determine the parameters that predicted recurrence in RHCC patients. The best cutoff value of NLR was determined with time-dependent receiver operating characteristic (ROC) curve analysis. The recurrence-free survival (RFS) rate was determined in patients with high and low NLR. RESULTS: The multivariate Cox proportional hazard model analysis showed that NLR was a prognostic factor in recurrence-free survival. NLR ≥ 2.14 was evaluated (AUROC = 0.824; P<0.001), and 183 of 506 patients (36.2%) had a NLR of more than 2.14. During the follow-up period (12-96 months), the 1-, and 3- year recurrence rates were 20.7% and 31.6% in low NLR group, respectively. These recurrence rates were significantly less than those in the high NLR group (57.9% and 82.5%, respectively) (P<0.001). A recurrence-free survival analyses demonstrated that the RFS in the low NLR group (67.2%) was significantly higher than that in the high NLR group (13.1%) (P<0.001). CONCLUSION: Our results show that preoperative NLR is a predictor for re-recurrence after thermal ablation in RHCC patients. Additionally, patients with NLR <2.14 have a lower recurrence rate, which may improve the clinical management of RHCC patients.

Percutaneous microwave ablation for liver tumours adjacent to the marginal angle.

PURPOSE: This study was designed to describe the technical essentials of microwave ablation (MWA) for tumours adjacent to the liver marginal angle (LMA) and to determine the feasibility, safety and efficacy of this approach. MATERIALS AND METHODS: A total of 22 patients with primary or metastatic liver tumours adjacent to the LMA were enrolled. There were 19 small tumours (≤3 cm) and three larger tumours (>3 cm) with maximum diameters ranging from 0.7-2.7 cm (mean 1.7 ± 0.6 cm) and 4.7-6.6 cm (mean 5.4 ± 1.0 cm), respectively. For small tumours the entire acute angle was segmentally blocked utilising MWA. For larger tumours, the feeding arteries were initially blocked with ethanol before conformal ablation. Artificial ascites, real-time monitoring, small ethanol doses, colour Doppler flow imaging or contrast enhanced ultrasound guidance was used as an additional technique to assist with ablation. Contrast imaging was performed to evaluate the ablative efficacy. Treatment responses, local tumour progression (LTP) and complications were recorded. RESULTS: All patients achieved a complete response. LTP was identified in two cases (9.1%) during the 4.5 month median follow-up period (range 2-29 months). A total of five additional sessions were performed, and secondary effectiveness was achieved in patients with LTP. No major complications were observed. CONCLUSIONS: Percutaneous MWA is a new promising technique for tumours adjacent to the LMA, especially in cases with small tumours. Technical improvements to this procedure are expected to improve the results for large tumours abutting the LMA.

A pyrene-based highly selective turn-on fluorescent chemosensor for iron(III) ions and its application in living cell imaging.

A new pyrene-based chemosensor (1) exhibits excellent selectivity for Fe(3+) ions over a wide range of tested metal ions Ag(+), Ca(2+), Cd(2+), Co(2+), Cu(2+), Fe(2+), Hg(2+), K(+), Mg(2+), Mn(2+), Ni(2+), Pb(2+), and Zn(2+). The binding of Fe(3+) to chemosensor 1 produces an emission band at 507 nm due to the formation of a Py-Py* excimer that is induced by Fe(3+)-binding. The binding ratio of 1-Fe(3+) was determined to be 1:1 from a Job plot. The association constant of 1-Fe(3+) complexes was found to be 1.27 × 10(4) M(-1) from a Benesi-Hildebrand plot. In addition, fluorescence microscopy experiments show that 1 can be used as a fluorescent probe for detecting Fe(3+) in living cells.

Hypochlorous acid turn-on fluorescent probe based on oxidation of diphenyl selenide.

A BODIPY-based fluorescent probe, HCSe, has been successfully developed for the rapid detection of hypochlorous acid based on the specific HOCl-promoted oxidation of diphenyl selenide in response to the amount of HOCl. Confocal fluorescence microscopy imaging using RAW264.7 cells showed that the new probe HCSe could be used as an effective fluorescent probe for detecting HOCl in living cells.

TLR2 is a primary receptor for Alzheimer's amyloid ß peptide to trigger neuroinflammatory activation.

Microglia activated by extracellularly deposited amyloid ß peptide (Aß) act as a two-edged sword in Alzheimer's disease pathogenesis: on the one hand, they damage neurons by releasing neurotoxic proinflammatory mediators (M1 activation); on the other hand, they protect neurons by triggering anti-inflammatory/neurotrophic M2 activation and by clearing Aß via phagocytosis. TLRs are associated with Aß-induced microglial inflammatory activation and Aß internalization, but the mechanisms remain unclear. In this study, we used real-time surface plasmon resonance spectroscopy and conventional biochemical pull-down assays to demonstrate a direct interaction between TLR2 and the aggregated 42-aa form of human Aß (Aß42). TLR2 deficiency reduced Aß42-triggered inflammatory activation but enhanced Aß phagocytosis in cultured microglia and macrophages. By expressing TLR2 in HEK293 cells that do not endogenously express TLR2, we observed that TLR2 expression enabled HEK293 cells to respond to Aß42. Through site-directed mutagenesis of tlr2 gene, we identified the amino acids EKKA (741-744) as a critical cytoplasmic domain for transduction of inflammatory signals. By coexpressing TLR1 or TLR6 in TLR2-transgenic HEK293 cells or silencing tlrs genes in RAW264.7 macrophages, we observed that TLR2-mediated Aß42-triggered inflammatory activation was enhanced by TLR1 and suppressed by TLR6. Using bone marrow chimeric Alzheimer's amyloid precursor transgenic mice, we observed that TLR2 deficiency in microglia shifts M1- to M2-inflammatory activation in vivo, which was associated with improved neuronal function. Our study demonstrated that TLR2 is a primary receptor for Aß to trigger neuroinflammatory activation and suggested that inhibition of TLR2 in microglia could be beneficial in Alzheimer's disease pathogenesis.

Myeloid differentiation factor 88-deficient bone marrow cells improve Alzheimer's disease-related symptoms and pathology.

Alzheimer's disease is characterized by extracellular deposits of amyloid ß peptide in the brain. Increasing evidence suggests that amyloid ß peptide injures neurons both directly and indirectly by triggering neurotoxic innate immune responses. Myeloid differentiation factor 88 is the key signalling molecule downstream to most innate immune receptors crucial in inflammatory activation. For this reason, we investigated the effects of myeloid differentiation factor 88-deficient bone marrow cells on Alzheimer's disease-related symptoms and pathology by establishing bone marrow chimeric amyloid ß peptide precursor transgenic mice, in which bone marrow cells differentiate into microglia and are recruited to amyloid ß peptide deposits. We observed that myeloid differentiation factor 88-deficient bone marrow reconstruction reduced both inflammatory activation and amyloid ß peptide burden in the brain. In addition, synaptophysin, a marker of neuronal integrity, was preserved and the expression of neuronal plasticity-related genes, ARC and NMDA-R1, was increased. Thus, myeloid differentiation factor 88-deficient microglia significantly improved the cognitive function of amyloid ß peptide precursor protein transgenic mice. Myeloid differentiation factor 88-deficiency enhanced amyloid ß peptide phagocytosis by microglia/macrophages and blunted toxic inflammatory activation. Both the expression of amyloid ß peptide precursor protein and amyloid ß peptide degrading enzymes and also the efflux of amyloid ß peptide from brain parenchyma were unaffected by myeloid differentiation factor 88-deficient microglia. By contrast, the activity of ß-secretase was increased. ß-Secretase is expressed primarily in neurons, with relatively little expression in astrocytes and microglia. Therefore, microglial replenishment with myeloid differentiation factor 88-deficient bone marrow cells might improve cognitive functions in Alzheimer's disease mouse models by enhancing amyloid ß peptide phagocytosis and reducing inflammatory activation. These results could offer a new therapeutic option that might delay the progression of Alzheimer's disease.

Expression of amyotrophic lateral sclerosis-linked SOD1 mutant increases the neurotoxic potential of microglia via TLR2.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease, in which activated microglia overexpressing ALS-linked SOD1 mutants (mSOD1) are known to contribute to neuronal death. However, it is unclear how mSOD1 expression affects micoglial activation and subsequently damages neurons. In this study, we created mSOD1-overexpressing BV-2 microglial cell lines. Following TLR2, but not TLR4 stimulation, we observed that overexpression of human SOD1 G93A, L8Q, or G10V mutant, as compared with the wild-type SOD1 or a mock control, significantly enhanced microglial secretion of a neurotoxic cytokine, tumor necrosis factor-alpha (TNF-alpha), which was dependent on the NADPH-oxidase-mediated increased generation of reactive oxygen species (ROS). In further experiments, we demonstrated that mSOD1 expression regulated TNF-alpha secretion at a post-transcriptional level and involved ROS-sensitive TNF-alpha-converting enzymes, e.g. ADAM10 and -17, which shed TNF-alpha from its membrane-anchored precursor. Together with a recent report that the function of SOD1, as a self-regulating redox sensor in NADPH oxidase-dependent ROS production, is lost due to its genetic mutations, we conclude that mSOD1 expression in ALS facilitates microglial neurotoxic inflammatory responses via TLR2, which is mediated by an uncontrolled ROS generation. The link, between mSOD1, innate immunity and NADPH oxidase, offers new opportunities in ALS therapies.

Identification and characterization of a novel thymus aging related protein Rwdd1.

By using DDRT-PCR and EST segment ligation, a novel mouse thymus involution related gene Rwdd1 was identified. The reading frame encoded a protein of 243 amino acid residues which contained an RWD domain at the N terminus. Rwdd1 expression in thymus was decreased in aged and oxidatively stressed mice. It was found to be expressed extensively in thymocytes and thymic epithelial cells. The expression level of Rwdd1 could affect the transactivation activity of androgen receptor (AR) in transiently transfected thymic epithelial cells. However, no direct interaction could be detected by fluorescence resonance energy transfer (FRET) analysis. In conclusion, Rwdd1 is a thymus involution related protein that may indirectly affect AR signaling pathway.