miR-145 as a Potential Biomarker and Therapeutic Target in Patients with Non-Small Cell Lung Cancer.

Our previous study found that miR-145 was downregulated in non-small cell lung cancer (NSCLC) tissues and that it could inhibit the cell proliferation in transfected NSCLC cells. In this study, we found that miR-145 was downregulated in NSCLC plasma samples compared to healthy controls. A receiver operating characteristic curve analysis indicated that plasma miR-145 expression was correlated with NSCLC in patient samples. We further revealed that the transfection of miR-145 inhibited the proliferation, migration, and invasion of NSCLC cells. Most importantly, miR-145 significantly delayed the tumor growth in a mouse model of NSCLC. We further identified GOLM1 and RTKN as the direct targets of miR-145. A cohort of paired tumors and adjacent non-malignant lung tissues from NSCLC patients was used to confirm the downregulated expression and diagnostic value of miR-145. The results were highly consistent between our plasma and tissue cohorts, confirming the clinical value of miR-145 in different sample groups. In addition, we also validated the expressions of miR-145, GOLM1, and RTKN using the TCGA database. Our findings suggested that miR-145 is a regulator of NSCLC and it plays an important role in NSCLC progression. This microRNA and its gene targets may serve as potential biomarkers and novel molecular therapeutic targets in NSCLC patients.

Automated Interictal Epileptiform Discharge Detection from Scalp EEG Using Scalable Time-series Classification Approaches.

Deep learning for automated interictal epileptiform discharge (IED) detection has been topical with many published papers in recent years. All existing works viewed EEG signals as time-series and developed specific models for IED classification; however, general time-series classification (TSC) methods were not considered. Moreover, none of these methods were evaluated on any public datasets, making direct comparisons challenging. This paper explored two state-of-the-art convolutional-based TSC algorithms, InceptionTime and Minirocket, on IED detection. We fine-tuned and cross-evaluated them on a public (Temple University Events - TUEV) and two private datasets and provided ready metrics for benchmarking future work. We observed that the optimal parameters correlated with the clinical duration of an IED and achieved the best area under precision-recall curve (AUPRC) of 0.98 and F1 of 0.80 on the private datasets, respectively. The AUPRC and F1 on the TUEV dataset were 0.99 and 0.97, respectively. While algorithms trained on the private sets maintained their performance when tested on the TUEV data, those trained on TUEV could not generalize well to the private data. These results emerge from differences in the class distributions across datasets and indicate a need for public datasets with a better diversity of IED waveforms, background activities and artifacts to facilitate standardization and benchmarking of algorithms.

Zinc-α2-glycoprotein is associated with non-albuminuric chronic kidney disease progression in type 2 diabetes: a retrospective study with 4-year follow-up.

AIM: To investigate the association between baseline plasma zinc-α2-glycoprotein and non-albuminuric chronic kidney disease progression in type 2 diabetes. METHODS: Adults with normoalbuminuria at entry (n=341; age 57±10 years, 52% men) were analysed. Chronic kidney disease progression was defined as a decrease in chronic kidney disease stage and a decline of ≥25% in estimated GFR from baseline. Baseline plasma zinc-α2-glycoprotein levels were quantified by immunoassay, and analysed either as a continuous variable or by tertiles in Cox proportional hazards models. Model discrimination was assessed using Harrell's C-index. A sensitivity analysis was performed on a subset of individuals who maintained normoalbuminuria during follow-up. RESULTS: Chronic kidney disease progression occurred in 54 participants (16%). Zinc-α2-glycoprotein levels were elevated in chronic kidney disease progressors (P = 0.011), and more progressors were assigned to the higher zinc-α2-glycoprotein tertile than non-progressors. In the unadjusted Cox model, zinc-α2-glycoprotein, both as a continuous variable (hazard ratio 1.72, 95% CI 1.08-2.75) and tertile 3 (vs tertile 1; hazard ratio 2.14, 95% CI 1.10-4.17), predicted chronic kidney disease progression. The association persisted after multivariable adjustment. The C-index of the Cox model increased significantly after incorporation of zinc-α2-glycoprotein into a base model comprising renin-angiotensin system antagonist usage. Sensitivity analysis showed that zinc-α2-glycoprotein independently predicted chronic kidney disease progression among individuals who maintained normoalbuminuria during follow-up. CONCLUSIONS: Plasma zinc-α2-glycoprotein is associated with chronic kidney disease progression, and may serve as a useful early biomarker for predicting non-albuminuric chronic kidney disease progression in type 2 diabetes.

Comparing two classification schemes for seizures and epilepsy in rural China.

BACKGROUND AND PURPOSE: The International League against Epilepsy (ILAE) updated the classifications of seizures and epilepsies in 2017. The 2017 classifications were compared with the 1980s classifications in rural China. METHODS: People with epilepsy receiving treatment under the National Epilepsy Control Programme were recruited from rural areas in China. Their seizures and epileptic syndrome were classified using the 1980s ILAE classification system and then re-classified according to the 2017 system. Differences in seizure, epilepsy and aetiology classifications were identified. RESULTS: A total of 597 individuals (58% males, aged 6-78 years) were included. Amongst them 535 (90%) had a single seizure type, 57 (9.55%) had two types and five (0.84%) had three. There was complete agreement between the 1981 and 2017 classifications for the 525 individuals with focal seizures. Seizures originally classified as generalized in 10 of 65 individuals were re-classified as unknown in the 2017 classification. Compared to the 1980s classifications, the proportion of individuals with unknown seizures and unknown epilepsy increased from 1.2% (7/597) to 2.8% (17/597, P = 0.002), and unknown aetiology increased from 32% (189/597: 182 cryptogenic and seven unclassified) to 39% (230/597; P < 0.001) in the 2017 classifications. CONCLUSIONS: The 1980s and 2017 classifications had 100% agreement in classifying focal seizures and epilepsy in rural China. A small but significant proportion of generalized seizures and epilepsy and aetiologies classified in the old classifications were re-classified to unknown in the new classifications. These results highlight the need for improvement in clinical evaluation of people with epilepsy in resource-poor settings.

SNP-based HLA allele tagging, imputation and association with antiepileptic drug-induced cutaneous reactions in Hong Kong Han Chinese.

Human leukocyte antigen (HLA) genes control the regulation of the human immune system and are involved in immune-related diseases. Population surveys on relationships between single nucleotide polymorphisms (SNP) and HLA alleles are essential to conduct genetic association between HLA variants and diseases. Samples were obtained from our in-house database for epilepsy genetics and pharmacogenetics research. Using 184 epilepsy patients with both genome-wide SNP array and HLA-A/B candidate gene sequencing data, we sought tagging SNPs that completely represent sixHLA risk alleles; in addition, a Hong Kong population-specific reference panel was constructed for SNP-based HLA imputation. The performance of our new panel was compared to a recent Han Chinese panel. Finally, genetic associations of HLA variants with mild skin rash were performed on the combined sample of 408 patients. Common SNPs rs2571375 and rs144295468 were found to successfully tag HLA risk alleles A*31:01 and B*13:01, respectively. HLA-B*15:02 can be predicted by rs144012689 with >95% sensitivity and specificity. The imputation reference panel for the Hong Kong population had comparable performance to the Han Chinese panel due to the large sample size for common HLA alleles, though it retained discordance for imputing rare alleles. No significant genetic associations were found between HLA genetic variants and mild skin rash induced by aromatic antiepileptic drugs. This study provides new information on the genetic structure of HLA regions in the Hong Kong population by identifying tagging SNPs and serving as a reference panel. Moreover, our comprehensive genetic analyses revealed no significant association between HLA alleles and mild skin rash in Hong Kong Han Chinese.

Sample-to-answer on molecular diagnosis of bacterial infection using integrated lab--on--a--disc.

Sepsis by bacterial infection causes high mortality in patients in intensive care unit (ICU). Rapid identification of bacterial infection is essential to ensure early appropriate administration of antibiotics to save lives of patients, yet the present benchtop molecular diagnosis is time-consuming and labor-intensive, which limits the treatment efficiency especially when the number of samples to be tested is extensive. Therefore, we hereby report a microfluidic platform lab-on-a-disc (LOAD) to provide a sample-to-answer solution. Our LOAD customized design of microfluidic channels allows automation to mimic sequential analytical steps in benchtop environment. It relies on a simple but controllable centrifugation force for the actuation of samples and reagents. Our LOAD system performs three major functions, namely DNA extraction, isothermal DNA amplification and real-time signal detection, in a predefined sequence. The disc is self-contained for conducting sample heating with chemical lysis buffer and silica microbeads are employed for DNA extraction from clinical specimens. Molecular diagnosis of specific target bacteria DNA sequences is then performed using a real-time loop-mediated isothermal amplification (RT-LAMP) with SYTO-9 as the signal reporter. Our LOAD system capable of bacterial identification of Mycobacterium tuberculosis (TB) and Acinetobacter baumanii (Ab) with the detection limits 103cfu/mL TB in sputum and 102cfu/mL Ab in blood within 2h after sample loading. The reported LOAD based on an integrated approach should address the growing needs for rapid point-of-care medical diagnosis in ICU.

Association between CYP2C19 Polymorphisms and Outcomes in Cerebral Endovascular Therapy.

BACKGROUND AND PURPOSE: Differing responses to clopidogrel following endovascular treatment of cerebrovascular diseases may increase the risk of vascular complications. CYP2C19 gene polymorphisms influence clopidogrel activity. We aimed to study the clinical impact of CYP2C19 gene polymorphisms in patients undergoing endovascular treatment. MATERIALS AND METHODS: This was a prospective, longitudinal, observational study. Information on demographics and cerebrovascular status was collected as baseline. Clopidogrel response was tested by the VerifyNow P2Y12 assay. CYP2C19 genotyping was undertaken by polymerase chain reaction-restriction fragment length polymorphism. Three-month follow-up data included vascular complications, mortality, and modified Rankin Scale score. Associations were investigated among CYP2C19 genotypes, clopidogrel responsiveness, and clinical outcomes. RESULTS: One hundred and eight participants were included. Median age was 56 years (interquartile range, 48.8-65.0 years), and 35 (32.4%) were male. Forty-four participants were classified into group 1 (homozygous CYP2C19*1/*1); 31, into group 2 (25 with CYP2C19*1/*2, two with CYP2C19*1/*3, three with CYP2C19*3/*3, one with CYP2C19*2/*3); 28, into group 3 (24 with CYP2C19*1/*17, four with CYP2C19*17/*17); and 5, into group 4 (CYP2C19*2/*17). A significantly higher proportion of participants in group 3 experienced ischemic events (9 of 28, 32.1%) compared with group 1 (5 of 44, 11.4%; P = .04; odds ratio, 3.7; 95% confidence interval, 1.1-12.6). There was no significant difference in clopidogrel response among the 4 genotype groups. CONCLUSIONS: Individuals with CYP2C19*17 may have increased risk of ischemic events following endovascular treatment, independent of clopidogrel responsiveness. Larger studies are required to confirm the influence of CYP2C19*17 on clinical outcomes and to understand the mechanisms for increased ischemic events.

Applying GIS and high performance agent-based simulation for managing an Old World Screwworm fly invasion of Australia.

Agent-based modelling has proven to be a promising approach for developing rich simulations for complex phenomena that provide decision support functions across a broad range of areas including biological, social and agricultural sciences. This paper demonstrates how high performance computing technologies, namely General-Purpose Computing on Graphics Processing Units (GPGPU), and commercial Geographic Information Systems (GIS) can be applied to develop a national scale, agent-based simulation of an incursion of Old World Screwworm fly (OWS fly) into the Australian mainland. The development of this simulation model leverages the combination of massively data-parallel processing capabilities supported by NVidia's Compute Unified Device Architecture (CUDA) and the advanced spatial visualisation capabilities of GIS. These technologies have enabled the implementation of an individual-based, stochastic lifecycle and dispersal algorithm for the OWS fly invasion. The simulation model draws upon a wide range of biological data as input to stochastically determine the reproduction and survival of the OWS fly through the different stages of its lifecycle and dispersal of gravid females. Through this model, a highly efficient computational platform has been developed for studying the effectiveness of control and mitigation strategies and their associated economic impact on livestock industries can be materialised.

Rapid detection of HLA-A*31:01 allele in DNA and blood samples using loop-mediated isothermal amplification.

BACKGROUND: The human leucocyte antigen (HLA) allele, HLA-A*31:01, is a biomarker for adverse cutaneous reactions to carbamazepine, a first-line antiepileptic drug. OBJECTIVES: To develop a platform that can rapidly detect the HLA-A*31:01 allele in blood samples to facilitate pretreatment screening. METHODS: A novel protocol based on loop-mediated isothermal amplification (LAMP) was designed and optimized. It was applied to purified genomic DNA samples derived from B-cell lines with known HLA genotypes, and to DNA and whole blood samples collected from patients with epilepsy, in whom HLA-A genotypes were determined by sequence-based typing. RESULTS: The turnaround time for the LAMP-based protocol was < 45 min. In the DNA samples derived from B-cell lines (n = 66), the sensitivity, specificity, positive predictive value and negative predictive value of the LAMP-based protocol for detecting HLA-A*31:01 were 1·00 [95% confidence interval (CI) 0·88-1·00], 0·95 (95% CI 0·82-0·99), 0·94 and 1·00, respectively. The LAMP-based protocol produced the same results in the DNA and whole blood samples collected from patients (n = 34). Its sensitivity, specificity, positive predictive value and negative predictive value in detecting HLA-A*31:01 in the patient samples were 1·00 (95% CI 0·57-1·00), 0·97 (95% CI 0·83-0·99), 0·83 and 1·00, respectively. CONCLUSIONS: The findings demonstrated the feasibility of accurately detecting HLA-A*31:01 in DNA and whole blood samples using a LAMP-based protocol. Given its rapid turnaround time, this novel platform has the potential to be adapted into a point-of-care screening test.

Curcumin modulation of high fat diet-induced atherosclerosis and steatohepatosis in LDL receptor deficient mice.

OBJECTIVE: Consuming curcumin may benefit health by modulating lipid metabolism and suppressing atherogenesis. Fatty acid binding proteins (FABP-4/aP2) and CD36 expression are key factors in lipid accumulation in macrophages and foam cell formation in atherogenesis. Our earlier observations suggest that curcumin's suppression of atherogenesis might be mediated through changes in aP2 and CD36 expression in macrophages. Thus, this study aimed to further elucidate the impact of increasing doses of curcumin on modulation of these molecular mediators on high fat diet-induced atherogenesis, inflammation, and steatohepatosis in Ldlr(-/-) mice. METHODS: Ldlr(-/-) mice were fed low fat (LF) or high fat (HF) diet supplemented with curcumin (500 HF + LC; 1000 HF + MC; 1500 HF + HC mg/kg diet) for 16 wks. Fecal samples were analyzed for total lipid content. Lipids accumulation in THP-1 cells and expression of aP2, CD36 and lipid accumulation in peritoneal macrophages were measured. Fatty streak lesions and expression of IL-6 and MCP-1 in descending aortas were quantified. Aortic root was stained for fatty and fibrotic deposits and for the expression of aP2 and VCAM-1. Total free fatty acids, insulin, glucose, triglycerides, and cholesterol as well as several inflammatory cytokines were measured in plasma. The liver's total lipids, cholesterol, triglycerides, and HDL content were measured, and the presence of fat droplets, peri-portal fibrosis and glycogen was examined histologically. RESULTS: Curcumin dose-dependently reduced uptake of oxLDL in THP-1 cells. Curcumin also reduced body weight gain and body fat without affecting fat distribution. During early intervention, curcumin decreased fecal fat, but at later stages, it increased fat excretion. Curcumin at medium doses of 500-1000 mg/kg diet was effective at reducing fatty streak formation and suppressing aortic expression of IL-6 in the descending aorta and blood levels of several inflammatory cytokines, but at a higher dose (HF + HC, 1500 mg/kg diet), it had adverse effects on some of these parameters. This U-shape like trend was also present when aortic root sections were examined histologically. However, at a high dose, curcumin suppressed development of steatohepatosis, reduced fibrotic tissue, and preserved glycogen levels in liver. CONCLUSION: Curcumin through a series of complex mechanisms, alleviated the adverse effects of high fat diet on weight gain, fatty liver development, dyslipidemia, expression of inflammatory cytokines and atherosclerosis in Ldlr(-/-) mouse model of human atherosclerosis. One of the mechanisms by which low dose curcumin modulates atherogenesis is through suppression of aP2 and CD36 expression in macrophages, which are the key players in atherogenesis. Overall, these effects of curcumin are dose-dependent; specifically, a medium dose of curcumin in HF diet appears to be more effective than a higher dose of curcumin.

Binational outbreak of Guillain-Barré syndrome associated with Campylobacter jejuni infection, Mexico and USA, 2011.

In June 2011, a cluster of suspected cases of Guillain-Barré syndrome (GBS), which can follow Campylobacter jejuni infection, was identified in San Luis Río Colorado (SLRC), Sonora, Mexico and Yuma County, Arizona, USA. An outbreak investigation identified 26 patients (18 from Sonora, eight from Arizona) with onset of GBS 4 May-21 July 2011, exceeding the expected number of cases (n = 1-2). Twenty-one (81%) patients reported antecedent diarrhoea, and 61% of 18 patients tested were seropositive for C. jejuni IgM antibodies. In a case-control study matched on age group, sex, ethnicity, and neighbourhood of residence, all Arizona GBS patients travelled to SLRC during the exposure period vs. 45% of matched controls (matched odds ratio 8·1, 95% confidence interval 1·5-∞). Exposure information and an environmental assessment suggested that GBS cases resulted from a large outbreak of C. jejuni infection from inadequately disinfected tap water in SLRC. Binational collaboration was essential in investigating this cross-border GBS outbreak, the first in mainland North America since 1976.

Manipulation of PBF/PTTG1IP phosphorylation status; a potential new therapeutic strategy for improving radioiodine uptake in thyroid and other tumors.

CONTEXT: The clinical effectiveness of ablative radioiodine treatment of thyroid tumors is limited by the availability of the sodium iodide symporter (NIS) at the plasma membrane (PM) for uptake of ¹³¹I. A significant proportion of well-differentiated thyroid tumors are unable to concentrate sufficient radioiodine for effective therapy, and in other tumor models such as breast tumors, where radioiodine uptake would be an attractive therapeutic option, uptake is insufficient. OBJECTIVE: Pituitary tumor-transforming gene-binding factor (PBF; PTTG1IP) is overexpressed in multiple cancers and significantly decreases NIS expression at the PM. The goal of this study was to identify a method by which PBF repression of NIS may be overcome in human tumors. RESULTS: Here, we identify PBF as a tyrosine phosphoprotein that specifically binds the proto-oncogene tyrosine protein kinase Src in mass spectrometry, glutathione S-transferase pulldown and coimmunoprecipitation assays. Src induction leads to phosphorylation at PBF residue Y174. Abrogation of this residue results in PM retention and a markedly reduced ability to bind NIS. The Src inhibitor PP1 inhibits PBF phosphorylation in multiple cell lines in vitro, including human primary thyroid cells. Of direct clinical importance to the treatment of thyroid cancer, PP1 stimulates iodide uptake by transfected NIS in TPC1 thyroid carcinoma cells and entirely overcomes PBF repression of iodide uptake in human primary thyroid cells. CONCLUSIONS: We propose that targeting PBF phosphorylation at residue Y174 via tyrosine kinase inhibitors may be a novel therapeutic strategy to enhance the efficacy of ablative radioiodine treatment in thyroid and other endocrine and endocrine-related tumors.

Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4.

AIMS/HYPOTHESIS: Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians. METHODS: We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations. RESULTS: We identified CDKN2A/B and four novel type 2 diabetes association signals with p < 1 × 10(-5) from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (p meta = 2.6 × 10(-8); OR [95% CI] 1.18 [1.11, 1.25]). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (p meta = 2.3 × 10(-10)) and a population of European descent (p = 8.6 × 10(-3)). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians. CONCLUSIONS/INTERPRETATION: Our study identifies rs10229583 near PAX4 as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.

Prediction for relapse and prognosis of newly diagnosed epilepsy.

OBJECTIVE: The objective of this study was to investigate the timing of therapy initiation and other clinical factors as potential predictors for relapse and prognosis of epilepsy, based on hospital-based prospective observational data in China. METHODS: One hundred and seventy-one newly diagnosed patients with one or more seizures were recruited and followed for at least 2 years. Kaplan-Meier survival analysis was used for calculating recurrence and remission rates. Univariate and multivariate analyses for risk factors were performed using Cox proportional hazards model. RESULTS: Among the 171 patients analyzed, more patients had partial (54.4%) than generalized seizures (45.6%). The range of patients' age was 6-70 years, but 70% were under 16 years of age. Multiple seizure types (HR = 2.01; 95% CI, 1.31-3.10), epileptiform electroencephalogram (EEG) abnormality (HR = 1.95; 95% CI, 1.09-3.49), and >1 seizure monthly before treatment (HR = 2.74; 95% CI, 1.69-4.51) were predictors of seizure recurrence. The best negative predictors of remission were as follows: relapse (HR = 0.13; 95% CI, 0.07-0.23) and epileptiform EEG within 1 year of treatment (HR = 0.61; 95% CI, 0.39-0.97). Delayed treatment after three or more seizures did not significantly increase the risk of recurrence (P = 0.70) or remission (P = 0.31) compared with early treatment after one or two seizures. CONCLUSIONS: Multiple seizure types, epileptiform EEG abnormality, and >1 seizure monthly before treatment predict seizure recurrence. Relapse and epileptiform EEG within 1 year of treatment predict adverse seizure outcome. Early treatment does not affect relapse or prognosis.

Patterns of treatment response in newly diagnosed epilepsy.

OBJECTIVE: To delineate the temporal patterns of outcome and to determine the probability of seizure freedom with successive antiepileptic drug regimens in newly diagnosed epilepsy. METHODS: Patients in whom epilepsy was diagnosed and the first antiepileptic drug prescribed between July 1, 1982, and April 1, 2006, were followed up until March 31, 2008. Outcomes were categorized into 4 patterns: (A) early and sustained seizure freedom; (B) delayed but sustained seizure freedom; (C) fluctuation between periods of seizure freedom and relapse; and (D) seizure freedom never attained. Probability of seizure freedom with successive drug regimens was compared. Seizure freedom was defined as no seizures for ≥1 year. RESULTS: A total of 1,098 patients were included (median age 32 years, range 9-93). At the last clinic visit, 749 (68%) patients were seizure-free, 678 (62%) on monotherapy. Outcome pattern A was observed in 408 (37%), pattern B in 246 (22%), pattern C in 172 (16%), and pattern D in 272 (25%) patients. There was a higher probability of seizure freedom in patients receiving 1 compared to 2 drug regimens, and 2 compared to 3 regimens (p < 0.001). The difference was greater among patients with symptomatic or cryptogenic than with idiopathic epilepsy. Less than 2% of patients became seizure-free on subsequent regimens but a few did so on their sixth or seventh regimen. CONCLUSIONS: Most patients with newly diagnosed epilepsy had a constant course which could usually be predicted early. The chance of seizure freedom declined with successive drug regimens, most markedly from the first to the third and among patients with localization-related epilepsies.

PTTG-binding factor (PBF) is a novel regulator of the thyroid hormone transporter MCT8.

Within the basolateral membrane of thyroid follicular epithelial cells, two transporter proteins are central to thyroid hormone (TH) biosynthesis and secretion. The sodium iodide symporter (NIS) delivers iodide from the bloodstream into the thyroid, and after TH biosynthesis, monocarboxylate transporter 8 (MCT8) mediates TH secretion from the thyroid gland. Pituitary tumor-transforming gene-binding factor (PBF; PTTG1IP) is a protooncogene that is up-regulated in thyroid cancer and that binds NIS and modulates its subcellular localization and function. We now show that PBF binds MCT8 in vitro, eliciting a marked shift in MCT8 subcellular localization and resulting in a significant reduction in the amount of MCT8 at the plasma membrane as determined by cell surface biotinylation assays. Colocalization and interaction between PBF and Mct8 was also observed in vivo in a mouse model of thyroid-specific PBF overexpression driven by a bovine thyroglobulin (Tg) promoter (PBF-Tg). Thyroidal Mct8 mRNA and protein expression levels were similar to wild-type mice. Critically, however, PBF-Tg mice demonstrated significantly enhanced thyroidal TH accumulation and reduced TH secretion upon TSH stimulation. Importantly, Mct8-knockout mice share this phenotype. These data show that PBF binds and alters the subcellular localization of MCT8 in vitro, with PBF overexpression leading to an accumulation of TH within the thyroid in vivo. Overall, these studies identify PBF as the first protein to interact with the critical TH transporter MCT8 and modulate its function in vivo. Furthermore, alongside NIS repression, PBF may thus represent a new regulator of TH biosynthesis and secretion.