Epidemiological connectivity between humans and animals across an urban landscape.

Urbanization is predicted to be a key driver of disease emergence through human exposure to novel, animal-borne pathogens. However, while we suspect that urban landscapes are primed to expose people to novel animal-borne diseases, evidence for the mechanisms by which this occurs is lacking. To address this, we studied how bacterial genes are shared between wild animals, livestock, and humans (n = 1,428) across Nairobi, Kenya-one of the world's most rapidly developing cities. Applying a multilayer network framework, we show that low biodiversity (of both natural habitat and vertebrate wildlife communities), coupled with livestock management practices and more densely populated urban environments, promotes sharing of Escherichia coli-borne bacterial mobile genetic elements between animals and humans. These results provide empirical support for hypotheses linking resource provision, the biological simplification of urban landscapes, and human and livestock demography to urban dynamics of cross-species pathogen transmission at a landscape scale. Urban areas where high densities of people and livestock live in close association with synanthropes (species such as rodents that are more competent reservoirs for zoonotic pathogens) should be prioritized for disease surveillance and control.

SR 57227A, a serotonin type-3 receptor agonist, as a candidate analgesic agent targeting nociplastic pain.

Pain is influenced by various factors, such as fear, anxiety, and memory. We previously reported that pain-like behaviors in mice can be induced by environmental cues in which a pain stimulus was previously presented, and that pain was reduced using fentanyl (an opioid). Although opioid analgesics are currently used to treat persistent pain, their inappropriate use causes a significant number of deaths in the United States. Thus, alternative medicines to opioids are needed. Here, we reported that SR 57227A, a serotonin type-3 receptor agonist, significantly reduced pain-like behaviors. The number of c-Fos positive cells increased by environmental cues in PFC was decreased by SR 57227A. Moreover, SR 57227A reduced pain-like behaviors of the formalin test, and restored reductions in paw withdrawal thresholds by acidic saline intramuscular injection and sciatic nerve ligation. Unlike opioids, SR 57227A induced no preference behaviors as measured by the conditioned place preference test. These data suggested that SR 57227A is an effective alternative pain reliever to opioids that targets chronic pain.

Programmed cell death ligand 1 measurement study in granulocyte colony-stimulating factor-producing lung cancer: an observational study.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF)-producing lung cancer induces severe inflammation and a high white blood cell (WBC) count and is associated with poor prognosis. A recent case of G-CSF-producing lung adenocarcinoma showed high expression of programmed cell death ligand 1 (PD-L1) and was treated with pembrolizumab as first-line therapy, which was extremely effective. We hypothesized that G-CSF-producing lung cancers are associated with high PD-L1 expression. METHODS: This retrospective study included patients diagnosed with lung cancer at Yokohama Municipal Citizen's Hospital (Kanagawa, Japan) between 2009 and 2019. The PD-L1 status of 13 patients with high plasma G-CSF levels (≥40 pg/mL) was assessed by conducting immunohistochemical analysis of tissue samples. RESULTS: Of the total patients, 11 were men and 2 were women, with a median age of 74 years (70-85 years). Four, five, and three patients had adenocarcinoma, squamous cell carcinoma, and others, respectively. The median G-CSF level and WBC count were 85.5 pg/mL (range, 40.8-484 pg/mL) and 15,550/µL (range, 6,190-56,800/µL), respectively. The PD-L1 tumor proportion scores (TPSs) were ≥50%, 1%-49%, and <1% in 9, 1, and 3 patients, respectively. The median overall survival time was 7.3 months. Pembrolizumab was administered in six patients as first-line treatment, with two patients showing partial response, one patient with stable disease, and three patients with progressive disease. All six patients had a PD-L1 TPS of ≥50%. CONCLUSION: G-CSF-producing lung cancers may be associated with increased PD-L1 expression. Although immune checkpoint inhibitors are an important treatment option for G-CSF-producing tumors, their effects are limited.

The Development and Evaluation of a Selective Enrichment for the Detection of Escherichia albertii in Food.

Escherichia albertii is an emerging pathogen causing foodborne infections with diarrhea, abdominal pain, and fever. E. albertii has been isolated from various food sources, such as chicken and pork. Although many foodborne outbreaks of E. albertii have been reported, the causative food has not been identified. It is necessary to develop effective detection methods for E. albertii. Because enrichment procedure as the first step of food test is important for growing pathogens, this study aimed to develop a novel effective enrichment for E. albertii detection in food. In this study, we investigated the optimal concentration and combination of cefixime and tellurite for supplementing modified EC broth (mEC) to effectively isolate E. albertii from chicken meat. The results showed that mEC supplemented with 50 µg/L cefixime and 2.5 mg/L tellurite (CT-mEC) inhibited the growth of competitive bacteria in chicken meat but not that of E. albertii. Therefore, it was indicated that CT-mEC had strong potential to selectively grow E. albertii. In an E. albertii foodborne outbreak, CT-mEC was evaluated. E. albertii was successfully isolated from a food sample, a kind of salad, by enrichment with CT-mEC but not buffered peptone water and mEC. In this study, CT-mEC as a selective enrichment broth has been developed to detect E. albertii in chicken meat. It was demonstrated that the selective enrichment broth was effective for the efficient detection of E. albertii in food.

Molecular Detection and Characterization of Rickettsia asembonensis in Human Blood, Zambia.

Rickettsia asembonensis is a flea-related Rickettsia with unknown pathogenicity to humans. We detected R. asembonensis DNA in 2 of 1,153 human blood samples in Zambia. Our findings suggest the possibility of R. asembonensis infection in humans despite its unknown pathogenicity.

Phase II study of amrubicin plus erlotinib in previously treated, advanced non-small cell lung cancer with wild-type epidermal growth factor receptor (TORG1320).

Background Amrubicin (AMR) is a completely synthetic 9-aminoanthracycline and clinically active against non-small cell lung cancer (NSCLC). We conducted a phase I study of AMR and erlotinib (ERL) combination therapy in previously treated patients with advanced NSCLC and have already reported the safety and effectiveness. Methods We conducted a multi-center, single-arm phase II trial to evaluate the efficacy of AMR and ERL combination therapy in patients with previously treated, advanced NSCLC harboring wild-type EGFR, PS 0-1 and < 75 years of age. Patients were treated at 3-week intervals with AMR plus ERL. The primary endpoint was the PFS, and the secondary endpoints were the response rate (RR), disease control rate (DCR), overall survival (OS) and toxicity. The trough ERL concentration (Ctrough) was measured as an exploratory study to analyze the relationship between the efficacy/safety and pharmacokinetics. Results From June 2013 to July 2016, 25 patients were enrolled in this trial. The PFS according to the central test was 3.6 months (95% confidence interval 2.1-5.1). The RR and DCR were 24.0% and 64.0%, respectively. We had no treatment-related deaths in this study. Conclusions The PFS of AMR and ERL combination therapy was superior to that of AMR monotherapy in the historical setting, but the primary endpoint was not met in this trial. In our study, the pharmacokinetic analysis showed that the Ctrough of ERL was elevated with combination therapy. This combination therapy might be a viable treatment for previously treated NSCLC patients without a driver oncogene mutation. Clinical trial information UMIN 000010582.

Effect of leaf temperature on the estimation of photosynthetic and other traits of wheat leaves from hyperspectral reflectance.

A growing number of leaf traits can be estimated from hyperspectral reflectance data. These include structural and compositional traits, such as leaf mass per area (LMA) and nitrogen and chlorophyll content, but also physiological traits such a Rubisco carboxylation activity, electron transport rate, and respiration rate. Since physiological traits vary with leaf temperature, how does this impact on predictions made from reflectance measurements? We investigated this with two wheat varieties, by repeatedly measuring each leaf through a sequence of temperatures imposed by varying the air temperature in a growth room. Leaf temperatures ranging from 20 °C to 35 °C did not alter the estimated Rubisco capacity normalized to 25 °C (Vcmax25), or chlorophyll or nitrogen contents per unit leaf area. Models estimating LMA and Vcmax25/N were both slightly influenced by leaf temperature: estimated LMA increased by 0.27% °C-1 and Vcmax25/N increased by 0.46% °C-1. A model estimating Rubisco activity closely followed variation associated with leaf temperature. Reflectance spectra change with leaf temperature and therefore contain a temperature signal.

Myostatin regulates pituitary development and hepatic IGF1.

Circulating myostatin-attenuating agents are being developed to treat muscle-wasting disease despite their potential to produce serious off-target effects, as myostatin/activin receptors are widely distributed among many nonmuscle tissues. Our studies suggest that the myokine not only inhibits striated muscle growth but also regulates pituitary development and growth hormone (GH) action in the liver. Using a novel myostatin-null label-retaining model (Jekyll mice), we determined that the heterogeneous pool of pituitary stem, transit-amplifying, and progenitor cells in Jekyll mice depletes more rapidly after birth than the pool in wild-type mice. This correlated with increased levels of GH, prolactin, and the cells that secrete these hormones, somatotropes and lactotropes, respectively, in Jekyll pituitaries. Recombinant myostatin also stimulated GH release and gene expression in pituitary cell cultures although inhibiting prolactin release. In primary hepatocytes, recombinant myostatin blocked GH-stimulated expression of two key mediators of growth, insulin-like growth factor (IGF)1 and the acid labile subunit and increased expression of an inhibitor, IGF-binding protein-1. The significance of these findings was demonstrated by smaller muscle fiber size in a model lacking myostatin and liver IGF1 expression (LID-o-Mighty mice) compared with that in myostatin-null (Mighty) mice. These data together suggest that myostatin may regulate pituitary development and function and that its inhibitory actions in muscle may be partly mediated by attenuating GH action in the liver. They also suggest that circulating pharmacological inhibitors of myostatin could produce unintended consequences in these and possibly other tissues.

SR 57227A is a partial agonist/partial antagonist of 5-HT3 receptor and inhibits subsequent 5-HT- or SR 57227A-induced 5-HT3 receptor current.

The serotonin (5-hydroxytryptamine) type 3 (5-HT3) receptors are transmembrane ligand-gated ion channels. Although several 5-HT3 receptor agonists have been used as preclinical tools, SR 57227A is the most commonly used 5-HT3 receptor agonist with the ability to cross the blood brain barrier. However, the precise pharmacological profile of SR 57227A remains unclear. Therefore, we examined the pharmacological profile of SR 57227A at the 5-HT3A and 5-HT3AB receptors. We microinjected Xenopus laevis oocytes with human 5-HT3A complementary RNA (cRNA) or a combination of human 5-HT3A and human 5-HT3AB cRNA and performed two electrode voltage clamp recordings of 5-HT3A and 5-HT3AB receptor current in the presence of SR 57227A. Results showed that SR 57227A acts as partial agonist/partial antagonist at the 5-HT3 receptor. Interestingly, SR 57227A specifically reduced subsequent current amplitudes induced by 5-HT or SR 57227A. Based on its 5-HT3 receptor partial agonist/partial antagonist properties, we predict that SR 57227A functions as a serotonin stabilizer.

Rat Model of Ménière's Attack: Intratympanic Injection of Potassium Chloride Produces Direction-Changing Spontaneous Nystagmus and Hearing Fluctuations.

The major symptoms of Ménière's disease are episodic vertigo, fluctuating hearing loss, and tinnitus. Direction-changing spontaneous nystagmus is a characteristic vestibular finding in Ménière's disease. In the acute stage, spontaneous nystagmus beating to the affected side (irritative nystagmus) is often observed, while paralytic nystagmus beating to the healthy side is found in the chronic stage. This direction-changing nystagmus can be reproduced in guinea pigs by increasing the potassium ion concentration in the perilymph. The objectives of the present study were to examine the effects of increasing the potassium ion concentration of the rat perilymph on hearing and nystagmus. Under isoflurane anesthesia, 22 rats received intratympanic injection of different concentrations of potassium chloride (KCl) solution or distilled water: groups 1, 2, 3, and 4 received saturated (3.4 M) KCl solution, 2 M KCl, 1 M KCl, and distilled water, respectively. The nystagmus direction and number per 15 s were monitored for 150 min. In the other 8 rats, hearing was monitored 30 min and 20 h after intratympanic injection of 2 M KCl (group 5) or distilled water (group 6) using the auditory brainstem responses. Rats in groups 1 and 2 showed spontaneous irritative nystagmus beating to the affected ear followed by paralytic nystagmus beating to the contralateral side. In group 3, irritative nystagmus occurred but paralytic nystagmus was rarely observed. Rats in group 4 showed no nystagmus. Rats in group 5 showed significant hearing impairment 30 min after KCl injection that recovered 20 h later. Control animals in group 6 showed no significant changes in hearing. The reversible hearing impairment with direction-changing spontaneous nystagmus induced by potassium injection into the tympanic cavity in rats was quite similar to that observed in acute Ménière's attacks. This rat model could be used for basic research investigating the pathophysiological mechanisms underlying Ménière's attacks.

Novel PHOX2B mutations in congenital central hypoventilation syndrome.

BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is caused by mutation of paird-like homeobox 2B (PHOX2B). Approximately 90% of patients were found to carry polyalanine repeat expansion mutation (PARM), and the remaining 10% had non-PARM (NPARM). In PARM, the length of the polyalanine expansion correlates with clinical disease severity. Most patients with NPARM have hypoventilation symptoms in the neonatal period and complications of Hirschsprung disease, dysregulation of autonomic nervous system, and tumors of neural crest origin. Data on the genotype-phenotype association may contribute to the clinical management of the disease. METHODS: We studied the genetic background of Japanese CCHS patients according to PHOX2B sequencing. RESULTS: Of 133 Japanese CCHS patients we identified 12 patients carrying 11 different NPARM (approx. 9% of the patients) and described the clinical manifestations in seven of them with the following novel mutations: c.941-945del5, c.678_693dup16, c.609_616del8, c.620_633del14, c.663_711del 49, c.448C>G and c.944G>C. All patients had hypoventilation in the neonatal period and also had Hirschsprung disease, with the exception of two patients carrying c.620_633del14 and c.663_711del49 mutations. The patient carrying the c.609_616del8 mutation also had a benign mediastinal tumor. CONCLUSION: Most patients carrying NPARM had severe symptoms with frequent complications, as in previous reports, and should be carefully monitored for various complications, including neural crest-derived tumor.

Molecular Components of Arabidopsis Intact Vacuoles Clarified with Metabolomic and Proteomic Analyses.

We analyzed the metabolites and proteins contained in pure intact vacuoles isolated from Arabidopsis suspension-cultured cells using capillary electrophoresis-mass spectrometry (CE-MS), Fourier transform-ion cyclotron resonance (FT-ICR)-MS and liquid chromatography (LC)-MS. We identified 21 amino acids and five organic acids as major primary metabolites in the vacuoles with CE-MS. Further, we identified small amounts of 27 substances including well-known vacuolar molecules, but also some unexpected substances (e.g. organic phosphate compounds). Non-target analysis of the vacuolar sample with FT-ICR-MS suggested that there are 1,106 m/z peaks that could predict the 5,090 molecular formulae, and we have annotated 34 compounds in these peaks using the KNapSAck database. By conducting proteomic analysis of vacuolar sap, we found 186 proteins in the same vacuole samples. Since the vacuole is known as a major degradative compartment, many of these were hydrolases, but we also found various oxidoreductases and transferases. The relationships between the proteins and metabolites in the vacuole are discussed.

Comparison of the efficacies of first-generation epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in patients with advanced non-small-cell lung cancer harboring EGFR mutations.

BACKGROUND: Compared with standard chemotherapy, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are more effective in patients with advanced non-small-cell lung cancer (NSCLC) harboring EGFR mutations. However, data comparing the efficacies of different EGFR-TKIs, especially regarding the presence of brain metastasis, are lacking. METHODS: EGFR-TKI naive patients with recurrent or stage IIIB/IV NSCLC harboring EGFR mutations, excluding resistance mutations, were enrolled in this study. We retrospectively determined progression-free survival (PFS) using the Kaplan-Meier method with log-rank test in patients treated with either gefitinib or erlotinib, cumulative incidence of central nervous system (CNS) progression using the Fine and Gray competing risk regression model, and favorable prognostic factors for CNS progression by multivariate analysis. RESULTS: Seventy-seven EGFR-TKI-naive patients were started on either gefitinib (n = 55) or erlotinib (n = 22) in our hospital from April 2010 to April 2016. Among the patients with brain metastasis, PFS tended to be longer in the erlotinib than in the gefitinib group. In the analysis of cumulative incidence, the probability of CNS progression was lower in the erlotinib group than in the gefitinib group. Particularly, in a subgroup analysis of the patients with brain metastasis, there was a significant difference between the erlotinib and gefitinib groups (hazard ratio 0.25; 95% confidence interval, 0.08-0.81; p = 0.021). Of the prognostic factors for CNS progression evaluated, the absence of brain metastasis before EGFR-TKI therapy and receiving erlotinib (vs gefitinib) had a significantly favorable effect on patient prognosis. CONCLUSION: Although this was a retrospective analysis involving a small sample size, erlotinib is potentially more promising than gefitinib for treatment of brain metastasis in patients with EGFR-mutant NSCLC.

Epiphycan is specifically expressed in cochlear supporting cells and is necessary for normal hearing.

The study of inner ear specific transcripts has revealed novel information about hereditary hearing loss and a mechanism of normal hearing. In this study, by analyzing a published cDNA library, we focused on Epiphycan (Epyc), a member of the small leucine-rich repeat proteoglycan family, whose transcript is enriched in the inner ear. Epyc mRNA was expressed abundantly and specifically in adult mice cochleae and was localized in supporting cells within the organ of Corti of both neonatal and adult mice. To examine the function of Epyc, we generated Epyc knockout (KO) mice using the CRISPR/Cas9 system. Epyc KO mice cochleae exhibited normal morphology. However, measurement of the auditory brain-stem response in Epyc KO mice revealed an elevated hearing threshold above 16 kHz frequency. This study suggests that Epyc is necessary for normal auditory function.

The Role of Nutritional Supplements in the Treatment of ADHD: What the Evidence Says.

Attention-deficit hyperactivity disorder (ADHD) is a common behavioral disorder in children and adolescents and may persist into adulthood. Insufficient nutritional supply of long-chain polyunsaturated fatty acids (LC-PUFAs) and other components including various minerals has been suggested to play a role in the development of ADHD symptoms. This review presents the evidence regarding the role of nutritional PUFA, zinc, iron, and magnesium supplements in the treatment of ADHD with a focus on the critical evaluation of the relevant literature published from 2014 to April 2016. The evaluation of therapeutic nutritional LC-PUFA supplementation in ADHD has shown mixed and inconclusive results and at best marginal beneficial effects. The benefits of PUFAs are much smaller than the effect sizes observed for traditional pharmacological treatments of ADHD. The effectiveness of PUFA supplements in reducing medication dosage has been suggested but needs to be confirmed. Zinc, iron, and magnesium supplementation may reduce ADHD symptoms in children with or at high risk of deficiencies in these minerals. However, convincing evidence in this regard is lacking.

Functional Expression of an Osmosensitive Cation Channel, Transient Receptor Potential Vanilloid 4, in Rat Vestibular Ganglia.

Transient receptor potential vanilloid (TRPV) 4 is a nonselective cation channel expressed in sensory neurons such as those in the dorsal root and trigeminal ganglia, kidney, and inner ear. TRPV4 is activated by mechanical stress, heat, low osmotic pressure, low pH, and phorbol derivatives such as 4α-phorbol 12,13-didecanoate (4α-PDD). We investigated the expression of TRPV4 in rat vestibular ganglion (VG) neurons. The TRPV4 gene was successfully amplified from VG neuron mRNA using reverse-transcription polymerase chain reaction. Furthermore, immunoblotting showed positive expression of TRPV4 protein in VG neurons. Immunohistochemistry indicated that TRPV4 was localized predominantly on the plasma membrane of VG neurons. Calcium (Ca2+) imaging of VG neurons showed that 4α-PDD and/or hypotonic stimuli caused an increase in intracellular Ca2+ concentration ([Ca2+]i) that was almost completely inhibited by ruthenium red, a selective antagonist of TRPV channels. Interestingly, a [Ca2+]i increase was evoked by both hypotonic stimuli and 4α-PDD in approximately 38% of VG neurons. These data indicate that TRPV4 is functionally expressed in VG neurons as an ion channel and that TRPV4 likely participates in VG neurons for vestibular neurotransmission as an osmoreceptor and/or mechanoreceptor.

Factors associated with antisocial behavior in patients with developmental disorder.

Objective: This study investigated the factors associated with antisocial behavior (AB) in children with developmental disorder and effective treatments. Methods: Participants were 110 schoolchildren with developmental disorder and with or without accompanying AB who visited our hospital between October 2009 and October 2012. Among the children with AB, those who exhibited one or more symptoms of conduct disorder (CD) were assigned to the CD subgroup. We examined the background characteristics, past history, type of antisocial behavior, and symptom improvement after treatment in the children with AB and compared the relevant factors with children with developmental disorder without AB. Results: Of the 110 participants, 72 (65.5%) did not exhibit AB and 38 (34.5%) did, 7 (5.5%) of whom fulfilled the criteria for CD. Compared to the children without AB, the children with AB showed a significantly higher occurrence of attention deficit/hyperactivity disorder (AD/HD), maltreatment, institutionalization due to maltreatment, parental mental/psychological problems, and family instability. After medical treatment combined with social-skills training and parental education, 22 of the 38 children with AB showed improved behavior. In the CD subgroup, 4 children were diagnosed with AD/HD and 3 with pervasive developmental disorder, and none of the 7 improved with treatment. Conclusion: AB was associated with AD/HD, maltreatment, institutionalization, parental mental/psychological problems, and family instability. The most effective therapy was parental education. Children with AB need early intervention given that those who already exhibited symptoms of CD showed little improvement with treatment.

The efficacy of amrubicin on central nervous system metastases originating from small-cell lung cancer: a case series of eight patients.

BACKGROUND: Central nervous system (CNS) metastases caused by small-cell lung cancer (SCLC) are incurable and therefore fatal. Although such metastases are usually treated with chemotherapy or radiotherapy, their sensitivity to these treatment measures is unclear. Amrubicin appears to be a promising agent for relapsed SCLC, but its effectiveness in CNS metastases originating from SCLC is unknown. METHODS: Between April 2002 and December 2009, 110 SCLC patients with CNS metastasis were treated at Shizuoka Cancer Center. Of these, we retrospectively reviewed 8 consecutive cases with CNS metastases originating from relapsed SCLC that were treated with amrubicin as a second-line therapy. RESULTS: We recorded three sensitive relapses and five refractory cases. Amrubicin yielded a CNS response rate of 50 % (2 partial responses and 2 complete response; 95 % CI, 21.5-78.5\ %) and the disease control rate for CNS lesions was 87.5 % (95 % CI, 52.9-97.8 %). All of the sensitive relapse patients achieved a partial response. The median time to progression for CNS metastases was 150.5 days (95 % CI, 9-171 days), and the median survival time from the start of amrubicin administration was 230.5 days (95 % CI, 89-619 days). We also report a dramatic improvement in one patient's radiological result of intramedullary spinal cord metastasis and alleviation of her symptoms following amrubicin monotherapy including this case series. CONCLUSIONS: The results of this study suggest that amrubicin is active in patients with CNS metastases originating from SCLC.

[A case of secondary sclerosing cholangitis caused by chemotherapy with nab-paclitaxel].

A 73-year-old woman had received 9 months of chemotherapy with nab-paclitaxel for locally advanced breast cancer. During the treatment, she was well and showed no major side effects except for alopecia and arthralgia. The tumor showed a tendency to reduction. However, chemotherapy was discontinued because of liver dysfunction. MRCP and ERCP demonstrated multiple stenoses of the hepatic ducts and the intrahepatic bile ducts. We diagnosed chemotherapy-induced sclerosing cholangitis caused by nab-paclitaxel. Treatment with ursodeoxycholic acid and steroid was ineffective. We added bezafibrate, which resulted in a gradual improvement in liver function. To the best of our knowledge, this is the first reported case of nab-paclitaxel-induced secondary sclerosing cholangitis.

Proteomics identified nuclear N-myc downstream-regulated gene 1 as a prognostic tissue biomarker candidate in renal cell carcinoma.

The aim of this study was to identify proteins with aberrant expression in clear cell renal cell carcinoma (ccRCC), and elucidate their clinical utilities. The protein expression profiles of primary ccRCC tumor tissues and neighboring non-tumor tissues were obtained from 9 patients by two-dimensional difference gel electrophoresis and mass spectrometry. Comparative analysis of 3771 protein spots led to the identification of 73 proteins that were expressed at aberrant levels in tumor tissues compared with non-tumor tissues. Among these 73 proteins, we further focused on N-myc downstream-regulated gene 1 protein (NDRG1). NDRG1 expression is regulated by members of myc family as well as by p53, HIF1A, and SGK1. The biological and clinical significance of NDRG1 is controversial for various malignancies and no detailed studies on NDRG1 have been reported in ccRCC until our study. For the 82 newly enrolled ccRCC patients, immunohistochemical analysis revealed a significant association between nuclear NDRG1 and favorable prognosis (p<0.05). Multivariate analysis demonstrated the role of NDRG1 as an independent factor of progression-free survival (p=0.01). Subsequent in vitro gene suppression assay demonstrated that NDRG1 silencing significantly enhanced cell proliferation and invasion of RCC cells. The cytotoxic effects of NDRG1 up-regulation induced by an iron chelator were also confirmed. These findings suggest that nuclear NDRG1 has tumor suppressive effects, and the NDRG1 expression may have clinical values in ccRCC. Nuclear NDRG1 may provide additional insights on molecular backgrounds of ccRCC progression, and contribute to the development of novel therapeutic strategy.