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1.  Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma 
Cell  2013;152(5):1065-1076.
SUMMARY
Medulloblastoma is the most common pediatric malignant brain tumor. Although current therapies improve survival, these regimens are highly toxic and associated with significant morbidity. Here, we report that placental growth factor (PlGF) is expressed in the majority of medulloblastomas independent of their subtype. Moreover, high expression of PlGF receptor neuropilin 1 (Nrp1) correlates with poor overall survival in patients. We demonstrate that PlGF and Nrp1 are required for the growth and spread of medulloblastoma: PlGF/Nrp1 blockade results in direct antitumor effects in vivo, resulting in medulloblastoma regression, decreased metastases, and increased mouse survival. We reveal that PlGF is produced in the cerebellar stroma via tumor-derived Sonic hedgehog (Shh) and show that PlGF acts through Nrp1—and not vascular endothelial growth factor receptor 1 (VEGFR1)—to promote tumor cell survival. This critical tumor-stroma interaction—mediated by Shh, PlGF, and Nrp1 across medulloblastoma subtypes—supports the development of therapies targeting PlGF/Nrp1 pathway.
doi:10.1016/j.cell.2013.01.036
PMCID: PMC3587980  PMID: 23452854
2.  Compact high-quality CdSe/CdS core/shell nanocrystals with narrow emission linewidths and suppressed blinking 
Nature materials  2013;12(5):445-451.
High particle uniformity, high photoluminescence quantum yields, narrow and symmetric emission spectral lineshapes and minimal single dot emission intermittency (known as blinking) have been recognized as universal requirements for the successful use of colloidal quantum dots (QDs) in nearly all optical applications. However, synthesizing samples that simultaneously meet all these four criteria has proven challenging. Here, we report the synthesis of such high-quality CdSe/CdS core/shell QDs in an optimized process which maintains a slow growth rate of the shell through the use of octanethiol and cadmium oleate as precursors. In contrast with previous observations, single-QD blinking is significantly suppressed with only a relatively thin shell. In addition, we demonstrate the elimination of the ensemble luminescence photodarkening that is an intrinsic consequence of QD blinking statistical aging. Furthermore, the small size and high photoluminescence quantum yields of these novel QDs render them superior in vivo imaging agents compared to conventional QDs. We anticipate that this new generation of QDs will also result in significant improvement in the performance of QDs in other applications such as solid-state lighting and illumination.
doi:10.1038/nmat3539
PMCID: PMC3677691  PMID: 23377294
3.  Spatial charge configuration regulates nanoparticle transport and binding behavior in vivo 
Detailed Charge arrangements: A new set of zwitterionic quantum dots were synthesized and used to study the influence of microscopic charge arrangements on the in vivo behavior of nanoparticles. Experiments using cultured cells and live mice demonstrate that the microscopic arrangement of surface charges strongly influence nonspecific binding, clearance behavior, and in vivo transport of nanoparticles.
doi:10.1002/anie.201208331
PMCID: PMC3755124  PMID: 23255143
Cancer; Ligand design; Nanoparticles; Quantum dots; Zwitterions
4.  In Vivo Imaging of Tumors 
Cold Spring Harbor protocols  2010;2010(7):pdb.prot5452.
PMCID: PMC3891051  PMID: 20647356
5.  Cationic Nanoparticles Have Superior Transvascular Flux into Solid Tumors: Insights from a Mathematical Model 
Annals of biomedical engineering  2012;41(1):10.1007/s10439-012-0630-4.
Despite their great promise, only a few nanoparticle formulations have been approved for clinical use in oncology. The failure of nano-scale drugs to enhance cancer therapy is in large part due to inefficient delivery. To overcome this outstanding problem, a better understanding of how the physical properties (i.e., size, surface chemistry, and shape) of nanoparticles affect their transvascular transport in tumors is required. In this study, we developed a mathematical model for nanoparticle delivery to solid tumors taking into account electrostatic interactions between the particles and the negatively-charged pores of the vessel wall. The model predictions suggest that electrostatic repulsion has a minor effect on the transvascular transport of nanoparticles. On the contrary, electrostatic attraction, caused even by small cationic charges (surface charge density less than 3 × 10−3 C/m2) can lead to a twofold or more increase in the transvascular flux of nanoparticles into the tumor interstitial space. Importantly, for every nanoparticle size, there is a value of charge density above which a steep increase in transvascular transport is predicted. Our model provides important guidelines for the optimal design of nanoparticle formulation for delivery to solid tumors.
doi:10.1007/s10439-012-0630-4
PMCID: PMC3886728  PMID: 22855118
Vascular permeability; Electrostatic and hydrodynamic interactions; Surface charge density; Nanomedicine; Cancer therapy
6.  Histological subtypes and characteristic structures of HPV-associated oropharyngeal carcinoma; study with Japanese cases 
Diagnostic Pathology  2013;8:211.
Background
Human papillomavirus-associated oropharyngeal carcinoma (HPV-OPC) is clinicopathologically distinct entity from the HPV-unassociated one (nHPV-OPC). This study aimed to determine the relationship between histological subtypes of OPC and HPV status for Japanese cases and to identify histological structures of HPV-OPC.
Methods
66 OPC cases were categorized into conventional squamous cell carcinoma (SCC) and the variants. Conventional SCC was subcategorized into keratinizing (KSCC), non-keratinizing (NKSCC), and hybrid SCC (HSCC). HPV status of all cases was determined using p16-immunohistochemistry and HPV-DNA ISH.
Results
Two histological subtypes, NKSCC and HSCC, tended to be HPV-OPC and KSCC tended to be nHPV-OPC with statistical significance. Two histological structures, abrupt keratinization, defined in the text, and comedo-necrosis among non-maturing tumor island, were observed for 58.1% and 38.7% of HPV-OPC, and tended to exist for HPV-OPC with statistical significance.
Conclusions
This study showed the association of NKSCC/HSCC with HPV-OPC in Japanese cases, and two histological structures, abrupt keratinization and comedo-necrosis among non-maturing island, were considered characteristic histological features of HPV-OPC.
Virtual slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1816432541113073.
doi:10.1186/1746-1596-8-211
PMCID: PMC3878250  PMID: 24354780
Human papillomavirus-associated oropharyngeal carcinoma; Non-keratinizing squamous cell carcinoma; Abrupt keratinization; Comedo-necrosis among non-maturing island
7.  Video-rate resonant scanning multiphoton microscopy 
Intravital (Print)  2012;1(1):10.4161/intv.21557.
The abnormal tumor microenvironment fuels tumor progression, metastasis, immune suppression, and treatment resistance. Over last several decades, developments in and applications of intravital microscopy have provided unprecedented insights into the dynamics of the tumor microenvironment. In particular, intravital multiphoton microscopy has revealed the abnormal structure and function of tumor-associated blood and lymphatic vessels, the role of aberrant tumor matrix in drug delivery, invasion and metastasis of tumor cells, the dynamics of immune cell trafficking to and within tumors, and gene expression in tumors. However, traditional multiphoton microscopy suffers from inherently slow imaging rates—only a few frames per second, thus unable to capture more rapid events such as blood flow, lymphatic flow, and cell movement within vessels. Here, we report the development and implementation of a video-rate multiphoton microscope (VR-MPLSM) based on resonant galvanometer mirror scanning that is capable of recording at 30 frames per second and acquiring intravital multispectral images. We show that the design of the system can be readily implemented and is adaptable to various experimental models. As examples, we demonstrate the utility of the system to directly measure flow within tumors, capture metastatic cancer cells moving within the brain vasculature and cells in lymphatic vessels, and image acute responses to changes in a vascular network. VR-MPLSM thus has the potential to further advance intravital imaging and provide new insight into the biology of the tumor microenvironment.
doi:10.4161/intv.21557
PMCID: PMC3864876  PMID: 24353926
video-rate; multiphoton; tumor microenvironment; vessels; metastasis; lymphatics
8.  A case of bilateral renal cell carcinoma associated with long-term dialysis showing false-positive immunoreactivity for TFE3 as Xp11 translocation renal cell carcinoma 
Renal carcinomas associated with Xp11.2 translocations/transcription factor 3 (TFE3) gene fusion (Xp11 translocation RCC) are a rare subtype of renal cell carcinoma. A middle-aged Japanese man, who had a medical history of dialysis for more than 12 years, had bilateral renal cancers with a background of acquired cystic disease of the kidney and remarkable deposition of calcium oxalate in the tumorous area. The right renal tumor showed papillary architecture of clear cells with diffuse and strong immunoreactivity for TFE3 and focal and weak positivity for cathepsin K, suggesting a possibility of Xp11 translocation RCC. However, RT-PCR failed to detect any type of the reported fusion genes involving TFE3. Thus, the sample was sent for a TFE3 break-apart FISH assay in a renal tumor consultation service, which reported no evidence of TFE3 gene rearrangement. The right renal tumor was finally diagnosed as papillary renal cell carcinoma with cystic change. We report here a case of bilateral renal cell carcinoma in a patient undergoing long-term dialysis, which showed false-positive immunoreactivity for TFE3 immunostaining. Titration of TFE3 immunohistochemical staining (IHC) should be performed and cross-referenced wcith the FISH or RT-PCR results to avoid the misinterpretation of TFE3 IHC results.
PMCID: PMC3816831  PMID: 24228124
Bilateral renal cell carcinoma; long-term dialysis; TFE3 as Xp11 translocation; FISH; RT-PCR
9.  Multistage Nanoparticles for Improved Delivery into Tumor Tissue 
Methods in enzymology  2012;508:109-130.
The enhanced permeability and retention (EPR) effect has been a key rationale for the development of nanoscale carriers to solid tumors. As a consequence of EPR, nanotherapeutics are expected to improve drug and detection probe delivery, have less adverse effects than conventional chemotherapy, and thus result in improved detection and treatment of tumors. Physiological barriers posed by the abnormal tumor microenvironment, however, can hinder the homogeneous delivery of nanomedicine in amounts sufficient to eradicate cancer. To effectively enhance the therapeutic outcome of cancer patients by nanotherapeutics, we have to find ways to overcome these barriers. One possibility is to exploit the abnormal tumor microenvironment for selective and improved delivery of therapeutic agents to tumors. Recently, we proposed a multistage nanoparticle delivery system as a potential means to enable uniform delivery throughout the tumor and improve the efficacy of anticancer therapy. Here, we describe the synthesis of a novel multistage nanoparticle formulation that shrinks in size once it enters the tumor interstitial space to optimize the delivery to tumors as well as within tumors. Finally, we provide detailed experimental methods for the characterization of such nanoparticles.
doi:10.1016/B978-0-12-391860-4.00006-9
PMCID: PMC3774840  PMID: 22449923
11.  The effect of adaptive iterative dose reduction on image quality in 320-detector row CT coronary angiography 
The British Journal of Radiology  2012;85(1016):e378-e382.
Objective
To evaluate the effect of adaptive iterative dose reduction (AIDR) on image noise and image quality as compared with standard filtered back projection (FBP) in 320-detector row CT coronary angiography (CTCA).
Methods
50 patients (14 females, mean age 68±9 years) who underwent CTCA (100 kV or 120 kV, 400–580 mA) within a single heartbeat were enrolled. Studies were reconstructed with FBP and subsequently AIDR. Image noise, vessel contrast and contrast-to-noise ratio (CNR) in the coronary arteries were evaluated. Overall image quality for coronary arteries was assessed using a five-point scale (1, non-diagnostic; 5, excellent).
Results
All the examinations were performed in a single heartbeat. Image noise in the aorta was significantly lower in data sets reconstructed with AIDR than in those reconstructed with FBP (21.4±3.1 HU vs 36.9±4.5 HU; p<0.001). No significant differences were observed between FBP and AIDR for the mean vessel contrast (HU) in the proximal coronary arteries. Consequently, CNRs in the proximal coronary arteries were higher in the AIDR group than in the FBP group (p<0.001). The mean image quality score was improved by AIDR (3.75±0.38 vs 4.24±0.38; p<0.001).
Conclusion
The use of AIDR reduces image noise and improves image quality in 320-detector row CTCA.
doi:10.1259/bjr/10084599
PMCID: PMC3495581  PMID: 22253355
12.  Acetaldehyde-Derived Advanced Glycation End-Products Promote Alcoholic Liver Disease 
PLoS ONE  2013;8(7):e70034.
Background
Chronic ingestion of ethanol increases acetaldehyde and leads to the production of acetaldehyde-derived advanced glycation end-products (AA-AGE). We evaluated the toxicity of AA-AGE on hepatocytes and studied the role of AA-AGE in the pathogenesis of alcoholic liver disease (ALD).
Methods
Rat hepatocyte cultures were treated with N-ethyllysine (NEL) or AA-AGE and the cell viability was evaluated using MTT assay. Male Wistar rats were fed with liquid diet containing 5% ethanol for 8 weeks following normal diet for another 12 weeks. A group of animals was sacrificed at 4th, 6th, and 8th week and the remaining animals at 12th, 14th, 16th, 18th, and 20th week. The liver sections were stained for AA-AGE and 4-hydroxy-2-nonenal (4-HNE). Liver biopsy obtained from ALD patients was also stained for AA-AGE and 4-HNE.
Results
Hepatocyte viability was significantly reduced in cultures treated with AA-AGE compared to NEL treated or control cultures. Severe fatty degeneration was observed during chronic administration of ethanol increasing from 4–8 weeks. The staining of AA-AGE and 4-HNE was correlated with the degree of ALD in both rat and human. In rats, hepatic fatty degeneration was completely disappeared and the staining for both AA-AGE and 4-HNE returned to normal at 12th week of abstinence. Staining for AA-AGE and 4-HNE was completely absent in normal human liver.
Conclusions
The data demonstrated that AA-AGE is toxic to hepatocytes, but not NEL. Chronic ethanol ingestion produces AA-AGE and reactive oxygen species that contribute to the pathogenesis of ALD. Abstinence of alcohol results in complete disappearance of both AA-AGE and 4-HNE along with fatty degeneration suggesting that AA-AGE plays a significant role in the pathogenesis of ALD.
doi:10.1371/journal.pone.0070034
PMCID: PMC3724722  PMID: 23922897
13.  Cardiac Rehabilitation Increases Exercise Capacity with a Reduction of Oxidative Stress 
Korean Circulation Journal  2013;43(7):481-487.
Background and Objectives
Reactive oxygen species (ROS) mediate various signaling pathways that underlie vascular inflammation in atherogenesis and cardiovascular diseases. Cardiac rehabilitation (CR) has a variety of multiple beneficial effects, including anti-inflammatory effects. The purpose of the present study was to investigate the effects of CR on ROS in patients with cardiovascular diseases.
Subjects and Methods
The serum level of derivatives of reactive oxidative metabolites, an index of oxidative stress, was measured in 100 patients with cardiovascular diseases before, and, subsequently, 3 and 6 months after, CR. A biological antioxidant potential (BAP) test was applied to assess the antioxidant power of the serum.
Results
The resting reactive oxidative metabolite levels decreased 3-6 months after CR {pre: 351±97 Carratelli unit (CARR U), 3 months: 329±77 CARR U, 6 months: 325±63 CARR U, all p<0.01} with the increase of the percentage of the predicted values of V̇O2 peak and the percentage of the predicted values of V̇O2 at the anaerobic threshold (V̇O2 AT) and the decrease of the B-type natriuretic peptide (BNP). The BAP test and antioxidative/oxidative stress ratio increased 6 months after CR. The % changes of the antioxidative/oxidative stress ratio was positively correlated with the % changes of V̇O2 AT, and negatively correlated with the % changes of the BNP.
Conclusion
These results suggest that intensive supervised CR significantly improved exercise capacity, which may be attributable to an adaptive response involving more efficient oxidative metabolites or the increased capacity of endogenous anti-oxidative systems in patients with cardiovascular diseases.
doi:10.4070/kcj.2013.43.7.481
PMCID: PMC3744736  PMID: 23964295
Reactive oxygen species; Antioxidants; Exercise therapy; Oxygen consumption; Cardiovascular diseases
14.  A case of myxoid liposarcoma of the breast 
A 70-year-old woman visited a local hospital complaining of a nodulein the right breast, present since 1 month. She was referred to our hospital for further evaluation. Following mammotome (MMT) biopsy, the nodule was diagnosed as myxoid/round cell liposarcoma. She underwent total mastectomy of the right breast. Histological analysis indicated that the tumor was almost entirely composed of proliferating small round mesenchymal cells in amyxoid matrix background with capillary-like vessels with partial necrosis (<10%). Immunohistochemically, p53 positive cells were seen focally (<1%) only, and the Ki-67 labeling index was approximately 20%. Sincethe surgical margin was histologically positive despite pathologic findings of high-grade malignancy, adjuvant treatment involving local radiation therapy (60Gy) was administered. The patient was free from any symptoms of local recurrence and metastases 1 year and 8 months after surgery.
PMCID: PMC3693211  PMID: 23826427
Myxoid liposarcoma; round cell component; breast
15.  Fatty Acid Synthase Is a Key Target in Multiple Essential Tumor Functions of Prostate Cancer: Uptake of Radiolabeled Acetate as a Predictor of the Targeted Therapy Outcome 
PLoS ONE  2013;8(5):e64570.
Fatty acid synthase (FASN) expression is elevated in several cancers, and this over-expression is associated with poor prognosis. Inhibitors of FASN, such as orlistat, reportedly show antitumor effects against cancers that over-express FASN, making FASN a promising therapeutic target. However, large variations in FASN expression levels in individual tumors have been observed, and methods to predict FASN-targeted therapy outcome before treatment are required to avoid unnecessary treatment. In addition, how FASN inhibition affects tumor progression remains unclear. Here, we showed the method to predict FASN-targeted therapy outcome using radiolabeled acetate uptake and presented mechanisms of FASN inhibition with human prostate cancer cell lines, to provide the treatment strategy of FASN-targeted therapy. We revealed that tumor uptake of radiolabeled acetate reflected the FASN expression levels and sensitivity to FASN-targeted therapy with orlistat in vitro and in vivo. FASN-targeted therapy was noticeably effective against tumors with high FASN expression, which was indicated by high acetate uptake. To examine mechanisms, we established FASN knockdown prostate cancer cells by transduction of short-hairpin RNA against FASN and investigated the characteristics by analyses on morphology and cell behavior and microarray-based gene expression profiling. FASN inhibition not only suppressed cell proliferation but prevented pseudopodia formation and suppressed cell adhesion, migration, and invasion. FASN inhibition also suppressed genes involved in production of intracellular second messenger arachidonic acid and androgen hormones, both of which promote tumor progression. Collectively, our data demonstrated that uptake of radiolabeled acetate is a useful predictor of FASN-targeted therapy outcome. This suggests that [1-11C]acetate positron emission tomography (PET) could be a powerful tool to accomplish personalized FASN-targeted therapy by non-invasive visualization of tumor acetate uptake and selection of responsive tumors. FASN-targeted therapy could be an effective treatment to suppress multiple steps related to tumor progression in prostate cancers selected by [1-11C]acetate PET.
doi:10.1371/journal.pone.0064570
PMCID: PMC3669310  PMID: 23741342
16.  Early diagnosis of asparaginase-associated pancreatitis based on elevated serum elastase-1 levels: Case reports 
Biomedical Reports  2013;1(4):651-653.
L-asparaginase (L-asp) is a well-known anticancer agent used in the treatment of acute lymphoblastic leukemia (ALL) in children. However, it is also known to induce several acute complications, such as acute pancreatitis. This is a presentation of two pediatric acute lymphoblastic leukemia (ALL) cases of asparaginase-associated pancreatitis (AAP) diagnosed at an early stage based on elevated serum elastase-1 levels, in the presence of normal serum amylase levels. Early diagnosis and treatment of AAP, although imperative, is occasionally difficult if only standard diagnostic procedures are followed. Elastase-1 is a potentially useful marker for the early diagnosis of AAP. Therefore, the measurement of elastase-1 levels, in addition to amylase and lipase levels, is recommended in L-asp-treated patients.
doi:10.3892/br.2013.108
PMCID: PMC3917048  PMID: 24649003
asparaginase; pancreatitis; elastase-1; acute lymphoblastic leukemia; chemotherapy
17.  NIRS external dose estimation system for Fukushima residents after the Fukushima Dai-ichi NPP accident 
Scientific Reports  2013;3:1670.
The great east Japan earthquake and subsequent tsunamis caused Fukushima Dai-ichi Nuclear Power Plant (NPP) accident. National Institute of Radiological Sciences (NIRS) developed the external dose estimation system for Fukushima residents. The system is being used in the Fukushima health management survey. The doses can be obtained by superimposing the behavior data of the residents on the dose rate maps. For grasping the doses, 18 evacuation patterns of the residents were assumed by considering the actual evacuation information before using the survey data. The doses of the residents from the deliberate evacuation area were relatively higher than those from the area within 20 km radius. The estimated doses varied from around 1 to 6 mSv for the residents evacuated from the representative places in the deliberate evacuation area. The maximum dose in 18 evacuation patterns was estimated to be 19 mSv.
doi:10.1038/srep01670
PMCID: PMC3628369  PMID: 23591638
18.  A transient parabiosis skin transplantation model in mice 
Nature Protocols  2012;7(4):763-770.
Parabiosis—conjoined surgery to provide a shared circulation between two mice—has been previously developed to study the hematopoietic system. This protocol describes the use of parabiosis for efficient transplantation of skin from a transgenic to a wild-type mouse. It can be used to study the role of stromal cells in a spontaneous model of distant cancer dissemination (metastasis). We have recently shown that primary tumor-derived stromal cells may facilitate metastasis by providing a provisional stroma at the secondary site. Studying the role of primary tumor–derived stroma cells requires methods for distinguishing and targeting stromal cells originating from the primary tumor versus their counterparts in the metastatic site. Parabiosis may also be used, taking advantage of the shared circulation between the parabiosed mice, to study tumor metastasis from one parabiont to another, or to investigate the role of circulating inflammatory cells or stem cells. Studying the role of stromal cells in metastasis using this model typically takes up to 11 weeks.
doi:10.1038/nprot.2012.032
PMCID: PMC3375333  PMID: 22441295
19.  An isolated tumor perfusion model in mice 
Nature Protocols  2012;7(4):749-755.
The role of stromal cells in the tumor microenvironment has been extensively characterized. We and others have shown that stromal cells may participate in several steps of the metastatic cascade. This protocol describes an isolated tumor perfusion model that enables studies of cancer and stromal cell shedding. It could also be used to study the effects of therapies interfering with the shedding of tumor cells or fragments, circulating (stem) cells or biomarkers. Primary tumors are grown in a microenvironment in which stromal cells express GFP ubiquitously. Tumors are implanted orthotopically or can be implanted ectopically. As a result, all tumor-associated stromal cells express GFP. This technique can be used to detect and study the role of stromal cells in tumor fragments within the circulation in mice. Studying the role of stromal cells in circulating tumor fragments using this model may take 2–10 weeks, depending on the growth rate of the primary tumor.
doi:10.1038/nprot.2012.030
PMCID: PMC3375334  PMID: 22441293
20.  Studying primary tumor–associated fibroblast involvement in cancer metastasis in mice 
Nature Protocols  2012;7(4):756-762.
Stromal cells have been studied extensively in the primary tumor microenvironment. In addition, mesenchymal stromal cells may participate in several steps of the metastatic cascade. Studying this interaction requires methods to distinguish and target stromal cells originating from the primary tumor versus their counterparts in the metastatic site. Here we illustrate a model of human tumor stromal cell—mouse cancer cell coimplantation. This model can be used to selectively deplete human stromal cells (using diphtheria toxin, DT) without affecting mouse cancer cells or host-derived stromal cells. Establishment of novel genetic models (e.g., transgenic expression of the DT receptor in specific cells) may eventually allow analogous models using syngeneic cells. Studying the role of stromal cells in metastasis using the model outlined above may take 8 weeks.
doi:10.1038/nprot.2012.031
PMCID: PMC3380105  PMID: 22441294
21.  Cancer imaging by optical coherence tomography: preclinical progress and clinical potential 
Nature reviews. Cancer  2012;12(5):363-368.
The last decade has seen dramatic technological advances in the field of optical coherence tomography (OCT) imaging. These advances have driven commercialization and clinical adoption in ophthalmology, cardiology, and gastrointestinal cancer screening. Recently an array of OCT-based imaging tools developed for preclinical intravital cancer imaging applications have yielded exciting new capabilities to probe and monitor cancer progression and response in vivo. Here, we review these results, forecast the future of OCT for preclinical cancer imaging and discuss its exciting potential to translate to the clinic as a tool for monitoring cancer therapy.
doi:10.1038/nrc3235
PMCID: PMC3560400  PMID: 22475930
22.  Comparison of the relationships of alcoholic and nonalcoholic fatty liver with hypertension, diabetes mellitus, and dyslipidemia 
We compared the relationships of alcoholic fatty liver and nonalcoholic fatty liver with hypertension, diabetes mellitus, and dyslipidemia. Using a nationwide Japanese survey, we collected data on subjects with biopsy-proven alcoholic fatty liver or nonalcoholic fatty liver. Multiple logistic regression analysis was performed to determine whether alcoholic fatty liver and nonalcoholic fatty liver are associated factors for these diseases. Data on 191 subjects (65, alcoholic fatty liver; 126, nonalcoholic fatty liver) were analyzed. Alcoholic fatty liver (odds ratio, 2.54; 95% confidence interval, 1.06–6.32; p = 0.040), age ≥55 years, and body mass index ≥25 kg/m2 were correlated with hypertension, whereas nonalcoholic fatty liver (odds ratio, 2.32; 95% confidence interval, 1.08–5.20; p = 0.035) and serum γ-glutamyl transpeptidase levels ≥75 IU/l were correlated with dyslipidemia. Furthermore, we found that there were biological interactions between alcoholic fatty liver and body mass index ≥25 kg/m2 in ≥55-year-old subjects (attributable proportion due to interaction, 0.68; 95% confidence interval, 0.19–1.17), as well as between alcoholic fatty liver and age ≥55 years in subjects with body mass index ≥25 kg/m2 (attributable proportion due to interaction, 0.71; 95% confidence interval, 0.24–1.18). Alcoholic fatty liver was more strongly associated with hypertension than nonalcoholic fatty liver and nonalcoholic fatty liver was more strongly associated with dyslipidemia than alcoholic fatty liver. Moreover, alcoholic fatty liver, obesity, and older age may interact to influence hypertension status.
doi:10.3164/jcbn.12-55
PMCID: PMC3541424  PMID: 23341703
alcoholic fatty liver; nonalcoholic fatty liver; hypertension; diabetes mellitus; dyslipidemia
23.  -449 C>G polymorphism of NFKB1 gene, coding nuclear factor-kappa-B, is associated with the susceptibility to ulcerative colitis 
AIM: To clarify the association between a polymorphism -449 C>G (rs72696119) in 5’-UTR of NFKB1 with ulcerative colitis (UC).
METHODS: The studied population comprised 639 subjects, including patients with UC (UC cases, n = 174) and subjects without UC (controls, n = 465). We employed polymerase chain reaction-single strand conformation polymorphism to detect the gene polymorphism.
RESULTS: The rs72696119 G allele frequencies in controls and UC cases were 33.4% and 38.5%, respectively (P = 0.10). Genotype frequency of the GG homozygote in UC cases was significantly higher than that in controls (P = 0.017), and the GG homozygote was significantly associated with susceptibility to UC [odds ratio (OR), 1.88; 95%CI, 1.13-3.14]. In male subjects, the GG homozygote was associated with an increased risk for UC (OR, 3.10; 95%CI, 1.47-6.54; P = 0.0053), whereas this association was not found in female subjects. In addition, the GG homozygote was significantly associated with the risk of non-continuous disease (OR, 2.06; 95%CI, 1.12-3.79; P = 0.029), not having total colitis (OR, 2.40; 95%CI, 1.09-3.80, P = 0.040), disease which developed before 20 years of age (OR, 2.80; 95%CI, 1.07-7.32, P = 0.041), no hospitalization (OR, 2.28; 95%CI, 1.29-4.05; P = 0.0090) and with a maximum of 8 or less on the UCDAI score (OR, 2.45; 95%CI, 1.23-4.93; P = 0.022).
CONCLUSION: Our results provide evidence that NFKB1 polymorphism rs72696119 was significantly associated with the development of UC. This polymorphism influences the susceptibility to and pathophysiological features of UC.
doi:10.3748/wjg.v18.i47.6981
PMCID: PMC3531683  PMID: 23322997
Genetic polymorphism; NFKB1; Ulcerative colitis
24.  Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner 
Nature nanotechnology  2012;7(6):383-388.
The blood vessels of cancerous tumours are leaky1–3 and poorly organized4–7. This can increase the interstitial fluid pressure (IFP) inside tumours and reduce blood supply to them, which impairs drug delivery8–9. Anti-angiogenic therapies – which “normalize” the abnormal blood vessels in tumours by making them less leaky – have been shown to improve the delivery and effectiveness of chemotherapeutics with low molecular-weights10, but it remains unclear whether normalizing tumour vessels can improve the delivery of nanomedicines. Here we show that repairing the abnormal vessels in mammary tumours, by blocking vascular endothelial growth factor (VEGF) receptor-2, improves the delivery of small nanoparticles (12nm diameter) while hindering the delivery of large nanoparticles (125nm diameter). We utilize a mathematical model to show that reducing vessel wall pore sizes through normalization decreases IFP in tumours, allowing small nanoparticles to enter them more rapidly. However, increased steric and hydrodynamic hindrances, also associated with smaller pores, make it more difficult for large nanoparticles to enter tumours. Our results further suggest that smaller (~12nm) nanomedicines are ideal for cancer therapy, owing to superior tumour penetration.
doi:10.1038/nnano.2012.45
PMCID: PMC3370066  PMID: 22484912
25.  Pro-apoptotic activity of inhibitory PAS domain protein (IPAS), a negative regulator of HIF-1, through binding to pro-survival Bcl-2 family proteins 
Cell Death and Differentiation  2011;18(11):1711-1725.
Inhibitory PAS (Per/Arnt/Sim) domain protein (IPAS) is a dominant negative transcription factor that represses hypoxia-inducible factor 1 (HIF-1) activity. In this study, we show that IPAS also functions as a pro-apoptotic protein through binding to pro-survival Bcl-2 family members. In a previous paper, we reported that NF-κB-dependent IPAS induction by cobalt chloride repressed the hypoxic response in PC12 cells. We found that prolonged incubation under the same conditions caused apoptosis in PC12 cells. Repression of IPAS induction protected cells from apoptosis. Furthermore, knockdown of IPAS recovered cell viability. EGFP-IPAS protein was localized in both the nucleus and the cytoplasm, with a large fraction associated with mitochondria. Mitochondrial IPAS induced mitochondria depolarization and caspase-3 activation. Immunoprecipitation assays revealed that IPAS is associated with Bcl-xL, Bcl-w and Mcl-1. The association of IPAS with Bcl-xL was also observed in living cells by the FLIM-based FRET analysis, indicating direct binding between the two proteins. IPAS contributed to dysfunction of Bcl-xL by inhibiting the interaction of Bcl-xL with Bax. These results demonstrate that IPAS functions as a dual function protein involved in transcription repression and apoptosis.
doi:10.1038/cdd.2011.47
PMCID: PMC3190112  PMID: 21546903
apoptosis; Bcl-xL; HIF-1alpha; IPAS

Results 1-25 (84)