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ABSTRACT: BACKGROUND: This study evaluated cervical lymph node metastases at level IIb in cases of hypopharyngeal cancer and analyzed the possibility of preservation of level IIb during neck dissection. METHODS: In total, 34 patients (51 neck sides) with hypopharyngeal cancer that underwent neck dissection from April 2008 to April 2011 were retrospectively analyzed. We evaluated the distribution of metastatic lymph nodes at various levels (particularly level IIb) in cases treated with therapeutic neck dissection and elective neck dissection. RESULTS: The incidence of metastases in level IIb was 13.3% (4 of 30 patients) for therapeutic neck dissection and 0% (0 of 21 patients) for elective neck dissection. All the level IIb metastases were found on the ipsilateral side in the cases treated with therapeutic neck dissection. CONCLUSIONS: The results suggest that preservation of level IIb during neck dissection was possible in N0 cases of hypopharyngeal cancer. © 2013 Wiley Periodicals, Inc. Head Neck, 2013.
Head & Neck 03/2013; · 2.40 Impact Factor
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Kenji Okami,
Koji Ebisumoto,
Akihiro Sakai,
Ryousuke Sugimoto,
Daisuke Maki, Kosuke Saito,
Shoji Kaneda,
Masahiro Iida,
Go Ogura,
Naoya Nakamura,
Koichiro Nishiyama
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ABSTRACT: BACKGROUND: The objective of this study was to evaluate the efficacy and safety of minimally invasive transoral en bloc resection of superficial pharyngeal and laryngeal cancers. METHODS: Forty-one superficial lesions (from 35 patients) were resected transorally under a surgical microscope using a monopolar cautery. Quality of life (QOL) was assessed using a questionnaire European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck Cancer Module (EORTC QLQ-H&N35) 1 year after the surgery. RESULTS: Twenty-eight hypopharyngeal, 5 oropharyngeal, and 8 laryngeal cancers were operated on using this method. The surgical field was widely exposed with a wide-caliber scope or extending laryngoscope. A bimanual procedure under a surgical microscope enabled us to achieve en bloc resection. The local control rate was 98%. No postoperative dyspnea or dysphagia was observed. Postoperative QOL scores were favorable. CONCLUSIONS: Our transoral en bloc resection technique can be easily adopted, and it effectively maintained QOL after treatment. © 2012 Wiley Periodicals, Inc. Head Neck, 2012.
Head & Neck 09/2012; · 2.40 Impact Factor
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Hiroyuki Matsuda,
Noboru Fukuda,
Takahiro Ueno,
Mayumi Katakawa,
Xiaofei Wang,
Takayoshi Watanabe,
Sei-Ichi Matsui,
Takahiko Aoyama, Kosuke Saito,
Toshikazu Bando,
Yoshiaki Matsumoto,
Hiroaki Nagase,
Koichi Matsumoto,
Hiroshi Sugiyama
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ABSTRACT: Pyrrole-imidazole (PI) polyamides are small synthetic molecules that recognize and attach to the minor groove of DNA, thereby inhibiting gene transcription by blocking transcription factor binding. These derivatives can act as gene silencers inhibiting target gene expression under stimulatory conditions such as disease. To evaluate PI polyamides as treatments for the progression of renal diseases, we examined morphological effects, pharmacological properties, and the specificity of PI polyamides targeted to the transforming growth factor (TGF)-β1 promoter during salt-induced hypertensive nephrosclerosis in Dahl salt-sensitive rats. The targeted PI polyamide markedly reduced glomerulosclerosis and interstitial fibrosis without side effects. PI polyamide significantly decreased expression of TGF-β1 and extracellular matrix in the renal cortex. Microarray analysis found that only 3% of the transcripts were affected by PI polyamide, but this included decreased expression of extracellular matrix, TGF-β1-related cytokines, angiogenic, and cell stabilizing factors, proteinases, and renal injury-related factors. Thus, targeted PI polyamides are potential gene silencers for diseases not treatable by current remedies.
Kidney International 01/2011; 79(1):46-56. · 6.61 Impact Factor
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ABSTRACT: Pyrrole-imidazole (PI) polyamide can bind to specific sequences in the minor groove of double-helical DNA and inhibit transcription of the genes. We designed and synthesized a PI polyamide to target the human connective tissue growth factor (hCTGF) promoter region adjacent to the Smads binding site. Among coupling activators that yield PI polyamides, 1-[bis(dimethylamino)methylene]-5-chloro-1H-benzotriazolium 3-oxide hexafluorophosphate (HCTU) was most effective in total yields of PI polyamides. A gel shift assay showed that a PI polyamide designed specifically for hCTGF (PI polyamide to hCTGF) bound the appropriate double-stranded oligonucleotide. A fluorescein isothiocyanate (FITC)-conjugated PI polyamide to CTGF permeated cell membranes and accumulated in the nuclei of cultured human mesangial cells (HMCs) and remained there for 48 h. The PI polyamide to hCTGF significantly decreased phorbol 12-myristate acetate (PMA)- or transforming growth factor-β1 (TGF-β1)-stimulated luciferase activity of the hCTGF promoter in cultured HMCs. The PI polyamide to hCTGF significantly decreased PMA- or TGF-β1-stimulated expression of hCTGF mRNA in a dose-dependent manner. The PI polyamide to hCTGF significantly decreased PMA- or TGF-β1-stimulated levels of hCTGF protein in HMCs. These results indicate that the developed synthetic PI polyamide to hCTGF could be a novel gene silencer for fibrotic diseases.
Biological & Pharmaceutical Bulletin 01/2011; 34(10):1572-7. · 1.66 Impact Factor
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ABSTRACT: Statins exert pleiotropic effects, including antioxidative and cellular protective effects. Endogenous adrenomedullin (AM) induces anti-inflammatory, anti-fibrotic and proangiogenic effects. We examined the effects of simvastatin on cardiac fibrosis and apoptosis in AM heterozygous knockout (AM(+/-)) mice treated with angiotensin (Ang) II and high salt loading. Seven-week-old AM(+/-) mice were infused with Ang II while on a high-salt diet with or without simvastatin for 2 weeks. Hearts were stained by hematoxylin-eosin or Masson's trichrome, and were immunostained with isolectin B(4) and α-smooth muscle actin antibodies. Expression of c-Kit and Sca-1 messenger RNA (mRNA) was evaluated by real-time PCR analysis. Apoptotic cells in hearts were identified by terminal deoxynucleotidyl transferase-mediated UTP end labeling (TUNEL) staining. Hearts from Ang II/salt loading AM(+/-) mice showed marked perivascular fibrosis around coronary arteries. Treatment with simvastatin significantly inhibited the fibrosis around coronary arteries in Ang II/salt-loading AM(+/-) mice. Expression of c-Kit and Sca-1 mRNAs in hearts from Ang II/salt-loading AM(+/-) mice was significantly lower than in hearts from wild-type mice. Treatment with simvastatin significantly increased the suppressed expression of c-Kit and Sca-1 mRNAs. In addition, treatment with simvastatin significantly increased the number of isolectin B(4)-positive capillary arteries in hearts from Ang II/salt-loading AM(+/-) mice. Ang II/high salt significantly increased apoptotic cells in hearts from AM(+/-) mice; this trend was reversed by treatment with simvastatin. Thus, statins have potent cardioprotective effects that may be associated with anti-fibrotic, proangiogenic and anti-apoptotic effects in Ang II/salt-loading AM(+/-) mice.
Hypertension Research 12/2010; 34(3):348-53. · 2.58 Impact Factor
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ABSTRACT: We hypothesized that one of the mechanisms underlying the protection of brain injury by therapeutic hypothermia is associated with preservation of neural stem cells. We investigated effects of moderate low temperature and the contribution of a cold-inducible molecule for the stemness of neural stem cells. The MEB5 mouse neural stem cell line was cultured in the presence or absence of EGF, and apoptosis, mRNA expression, and immunocytochemistry of the differentiation markers nestin and GFAP were evaluated at 37 or 32°C. We investigated the contribution of the cold-inducible RNA binding protein (CIRP) on apoptosis and differentiation of MEB5 cells at 32°C. EGF deprivation increased the number of apoptotic cells, decreased expression of nestin, and increased expression of GFAP. The moderate low temperature prevented apoptosis and decreases in expression of GFAP in MEB5 by EGF deprivation. The moderate low temperature significantly increased expression of CIRP. siRNA against CIRP significantly increased the apoptotic cell population of MEB5 cells via EGF deprivation at 32°C. These findings suggest that moderate low temperature preserved stemness of neural stem cells and prevented cell apoptosis via the stimulation of CIRP, and one of the mechanisms of rescue of brain injury by the moderate hypothermia is associated with preservation of neural stem cells.
Brain research 10/2010; 1358:20-9. · 2.46 Impact Factor
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Teruyuki Takahashi,
Yukihiro Asami,
Eiko Kitamura,
Tsukasa Suzuki,
Xiaofei Wang,
Jun Igarashi,
Aiko Morohashi,
Yui Shinojima,
Hisao Kanou, Kosuke Saito, [......],
Kazumichi Kuroda,
Takayoshi Watanabe,
Satoshi Kumamoto,
Takahiko Aoyama,
Yoshiaki Matsumoto,
Toshikazu Bando,
Hiroshi Sugiyama,
Chikako Yoshida-Noro,
Noboru Fukuda,
Nariyuki Hayashi
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ABSTRACT: Pyrrole-imidazole polyamide (PIP) is a nuclease-resistant novel compound that inhibits gene expression through binding to the minor groove of DNA. Human aurora kinase-A (AURKA) and -B (AURKB) are important regulators in mitosis during the cell cycle. In this study, two specific PIPs (PIP-A and PIP-B) targeting AURKA and AURKB promoter regions were designed and synthesized, and their biological effects were investigated by several in vitro assays. PIP-A and PIP-B significantly inhibited the promoter activities, mRNA expression, and protein levels of AURKA and AURKB, respectively, in a concentration-dependent manner. Moreover, 1:1 combination treatment with both PIPs demonstrated prominent antiproliferative synergy (CI value [ED(50)] = 0.256) to HeLa cells as a result of inducing apoptosis-mediated severe catastrophe of cell-cycle progression. The novel synthesized PIP-A and PIP-B are potent and specific gene-silencing agents for AURKA and AURKB.
Chemistry & Biology 09/2008; 15(8):829-41. · 5.83 Impact Factor
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Teruyuki Takahashi,
Masato Tamura,
Yukihiro Asami,
Eiko Kitamura, Kosuke Saito,
Tsukasa Suzuki,
Sachiko Nonaka Takahashi,
Koichi Matsumoto,
Shigemasa Sawada,
Eise Yokoyama,
Toshiaki Takasu
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ABSTRACT: Previously, we designed an internally controlled quantitative nested real-time (QNRT) PCR assay for Mycobacterium tuberculosis DNA in order to rapidly diagnose tuberculous meningitis. This technique combined the high sensitivity of nested PCR with the accurate quantification of real-time PCR. In this study, we attempted to improve the original QNRT-PCR assay and newly developed the wide-range QNRT-PCR (WR-QNRT-PCR) assay, which is more accurate and has a wider detection range. For use as an internal-control "calibrator" to measure the copy number of M. tuberculosis DNA, an original new-mutation plasmid (NM-plasmid) was developed. It had artificial random nucleotides in five regions annealing specific primers and probes. The NM-plasmid demonstrated statistically uniform amplifications (F = 1.086, P = 0.774) against a range (1 to 10(5)) of copy numbers of mimic M. tuberculosis DNA and was regarded as appropriate for use as a new internal control in the WR-QNRT-PSR assay. In addition, by the optimization of assay conditions in WR-QNRT-PCR, two-step amplification of target DNA was completely consistent with the standard curve of this assay. Due to the development of the NM-plasmid as the new internal control, significantly improved quantitative accuracy and a wider detection range were realized with the WR-QNRT-PCR assay. In the next study, we will try to use this novel assay method with actual clinical samples and examine its clinical usefulness.
Journal of clinical microbiology 06/2008; 46(5):1708-15. · 4.16 Impact Factor
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Teruyuki Takahashi,
Masato Tamura,
Yukihiro Asami,
Eiko Kitamura, Kosuke Saito,
Tsukasa Suzuki,
Sachiko Nonaka Takahashi,
Koichi Matsumoto,
Shigemasa Sawada,
Eise Yokoyama,
Toshiaki Takasu
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ABSTRACT: Although the "gold standard" for diagnosis of tuberculous meningitis (TBM) is bacterial isolation of Mycobacterium tuberculosis, there are still several complex issues. Recently, we developed an internally controlled novel wide-range quantitative nested real-time PCR (WR-QNRT-PCR) assay for M. tuberculosis DNA in order to rapidly diagnose TBM. For use as an internal control calibrator to measure the copy number of M. tuberculosis DNA, an original new-mutation plasmid (NM-plasmid) was developed. Due to the development of the NM-plasmid, the WR-QNRT-PCR assay demonstrated statistically significant accuracy over a wide detection range (1 to 10(5) copies). In clinical applications, the WR-QNRT-PCR assay revealed sufficiently high sensitivity (95.8%) and specificity (100%) for 24 clinically suspected TBM patients. In conditional logistic regression analysis, a copy number of M. tuberculosis DNA (per 1 ml of cerebrospinal fluid) of >8,000 was an independent risk factor for poor prognosis for TBM (i.e., death) (odds ratio, 16.142; 95% confidence interval, 1.191 to 218.79; P value, 0.0365). In addition, the copy numbers demonstrated by analysis of variance statistically significant alterations (P < 0.01) during the clinical treatment course for 10 suspected TBM patients. In simple regression analysis, the significant correlation (R(2) = 0.597; P < 0.0001) was demonstrated between copy number and clinical stage of TBM. We consider the WR-QNRT-PCR assay to be a useful and advanced assay technique for assessing the clinical treatment course of TBM.
Journal of clinical microbiology 05/2008; 46(5):1698-707. · 4.16 Impact Factor
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ABSTRACT: As aromatase-deficient mice, which are deficient in estrogens, reportedly have reduced blood pressure, the aromatase gene (CYP19A1) is thought to be a susceptibility gene for essential hypertension (EH). The aim of the present study was to investigate the relationship between CYP19A1 and EH by examining single nucleotide polymorphisms (SNPs).
Five SNPs in the human CYP19A1 gene (rs1870049, rs936306, rs700518, rs10046 and rs4646) were selected, and an association study was performed in 218 Japanese EH patients and 225 age-matched normotensive (NT) individuals.
There were significant differences between these groups in the distribution of genotypes rs700518 and rs10046 in male subjects, and genotypes rs700518, rs10046 and rs4646 in female subjects. On multiple logistic regression analysis, a significant association between rs700518 (p=0.023) and rs10046 (p=0.036) in male subjects and rs700518 in female subjects (p=0.018) was noted. Interestingly, the risk genotypes of rs700518 and rs10046 showed a sex-dependent inverse relationship. Both SBP and DBP levels were higher in total (cases and controls) male subjects with the G/G genotype with rs700518 or the T/T genotype with rs10046 than in male subjects without the G/G genotype or T/T genotype. SBP levels were lower in female subjects with the G/G genotype with rs700518 than in female subjects without G/G. The A-T haplotype constructed with rs1870049 and rs10046 was a susceptibility marker for EH.
We confirmed that rs700518 and rs10046, as well as a haplotype constructed with rs1870049 and rs10046, in the human CYP19A1 gene can be used as genetic markers for gender-specific EH.
International journal of medical sciences 02/2008; 5(1):29-35. · 2.24 Impact Factor
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Yukie Yoshikawa,
Tomohiro Nakayama, Kosuke Saito,
Peng Hui,
Akihiko Morita,
Naoyuki Sato,
Teruyuki Takahashi,
Masaaki Tamura,
Ichiro Sato,
Noriko Aoi,
Nobutaka Doba,
Shigeaki Hinohara,
Masayoshi Soma,
Ron Usami
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ABSTRACT: Uroguanylin (gene name: guanylate cyclase activator 2B, GUCA2B) is a peptide regulator of intestinal salt and water transport. It has been reported that the uroguanylin knockout mouse exhibits elevated blood pressure. Therefore, the GUCA2B gene is thought to be a susceptibility gene for essential hypertension (EH). Despite extensive studies, however, the relationship between the GUCA2B gene and EH has not yet been defined. The aim of this study was to assess the association between the human GUCA2B gene and EH. Using four single nucleotide polymorphisms (SNPs), we conducted a genetic association study in 281 EH patients and 279 age-matched normotensive (NT1) individuals. To derive more reliable data, we performed a duplicate case-control study in which we recruited another normotensive group (NT2). There was no significant difference in the overall distribution of alleles for any of the SNPs between the EH and NT1 groups, or between the EH and NT2 groups. Therefore, these four SNPs cannot be the genetic markers for EH. The occurrences of the C-A haplotype (rs883062-rs1047047) and the C-A-G haplotype (rs883062-rs1047047-rs2297566) were significantly higher in the EH group than in the NT1 group (p<0.0001) or the NT2 group (p<0.0001). These results suggest that the C-A haplotype and the C-A-G haplotype of the GUCA2B gene are the genetic markers for EH, and that GUCA2B or a neighboring gene might be a susceptibility gene for EH.
Hypertension Research 09/2007; 30(9):789-96. · 2.58 Impact Factor
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Peng Hui,
Tomohiro Nakayama,
Akihiko Morita,
Naoyuki Sato,
Mikano Hishiki, Kosuke Saito,
Yukie Yoshikawa,
Masaaki Tamura,
Ichiro Sato,
Teruyuki Takahashi,
Masayoshi Soma,
Yoichi Izumi,
Yukio Ozawa,
Zuheng Cheng
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ABSTRACT: Essential hypertension (EH) is a multifactorial disorder determined by the interaction of environmental and genetic factors. EH patients' responses to these factors may vary, depending on differences in their genes that determine the physiological systems that mediate the response. The purpose of this investigation was to clarify the contributions of genetic background and lifestyle to EH through an association study using some common single nucleotide polymorphisms (SNPs) that should have functional effects on EH phenotypes. We studied the associations between common SNPs of some causal genes related to EH and lifestyle in a Japanese population. The variants of the causal genes were selected based on their functions, including: obesity (adrenergic, beta-3-, receptor: ADRB3), alcohol consumption (aldehyde dehydrogenase 2: ALDH2), water-electrolyte metabolism (guanine nucleotide binding protein [G protein], beta polypeptide 3: GNB3), glycometabolism (peroxisome proliferator-activated receptor gamma: PPARG), lipometabolism (cholesteryl ester transfer protein, plasma: CETP), atherosclerosis (5,10-methylenetetrahydrofolate reductase [NADPH]: MTHFR), and cellular behavior (gap junction protein, alpha 4, 37 kD: GJA4). Case-control association analysis showed a significant association between EH and both the ALDH2 (Lys487Glu) and GNB3 (C825T) variants. Logistic regression analysis indicated that body mass index (BMI) is an important risk factor for EH, and that the GG (Glu/Glu) genotype of ALDH2 was an independent risk factor for EH overall and especially for EH in males. There was no interaction between the ALDH2 genotype and alcohol consumption overall or in male subjects. Our results suggest that the ALDH2 genotype is associated with EH independently of alcohol consumption.
Hypertension Research 08/2007; 30(7):585-92. · 2.58 Impact Factor
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ABSTRACT: Ischemic stroke (IS) is thought to be a multifactorial disorder associated with genetic backgrounds and environmental factors. In the circulating plasma, tissue plasminogen activator (tPA) catalyzes the reaction from plasminogen to plasmin. If there is a functional disability of tPA, induction of thrombosis and infarction disorders can occur. The aim of this study was to perform a haplotype-based case-control study using single nucleotide polymorphisms (SNPs) in the human tPA gene, and to assess the association between the tPA gene and IS. We genotyped 182 IS individuals and 403 controls for five SNPs in the human tPA gene, rs7007329, rs732612, rs8178750, rs2020922, and rs4471024. Using these five SNPs, a haplotype-based case control study was performed. There were seven SNP combinations that exhibited significant differences in the overall distribution between the IS and control groups. Linkage disequilibrium analysis showed that the combination of rs7007329 and rs8178750 was useful in identification of the susceptibility haplotype. The frequency of the G-T haplotype at rs7007329-rs8178750 was significantly higher in the IS group (1.2%) as compared to the control group (0.0%) (p = 0.003). Diplotype analysis also showed a significant association of the diplotype with the G-T haplotype at rs7007329-rs8178750 (OR:11.4, 95%CI:1.32-97.9, p = 0.013). These results suggest that the G-T haplotype at rs7007329-rs8178750 of the tPA gene is a genetic marker for IS, and that tPA or a neighboring gene is a susceptibility gene for IS.
Thrombosis and Haemostasis 10/2006; 96(3):331-6. · 5.04 Impact Factor
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ABSTRACT: The risk of cerebral infarction (CI) in an individual is dependent on the interplay between genetic risk factors and environmental influences. Binding of thromboxane A2 (TXA2) to its receptor (TP) modulates thrombosis/hemostasis and plays a significant role in the pathogenesis of CI. The aim of the present study was to investigate the relationship between human TP gene single nucleotide polymorphisms (SNPs) and haplotypes and CI in a Japanese population. A genetic association study was performed in 194 CI patients and 365 non-CI subjects by specifically characterizing 6 SNPs in the human TP gene (rs2271875, rs768963, rs2238634, rs11085026, rs4523 and rs4806942). Analysis demonstrated that there were significant differences in the overall distribution of genotypes and dominant or recessive models of rs2271875 and rs768963 between the CI and the non-CI groups. Multiple logistic regression analysis revealed that the C allele of rs768963 was significantly associated with CI (p = 0.029), even after adjusting for confounding factors (odds ratio: 2.41). Further, the C-T-C haplotype of rs768963-rs2238634-rs4806942 was significantly more frequent in the CI group (23.0%) than in the non-CI group (17.7%). These results suggest that specific SNPs and haplotypes may have utility as genetic markers for the risk of CI and that TP or a neighboring gene is associated with the increased susceptibility to CI.
Hypertension Research 10/2006; 29(9):665-71. · 2.58 Impact Factor
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ABSTRACT: AbstrAct Several previous studies have shown that essential hypertension (EH) is associated with fibrinolysis. Tissue plasminogen activator (t-PA) plays a key role in fibrinolysis. Thus, it is possible that the t-PA gene is a susceptibility gene of EH. However, there have been no reported studies of association between EH and the t-PA gene using single nucleotide polymorphisms (SNPs). The aim of the present haplotype-based case-con-trol study was to investigate whether SNPs in the human t-PA gene are associated with EH. We performed a genetic association study using 3 SNPs (rs7007329, rs8178750, rs4471024). The subjects were 276 EH patients and 283 age-matched normotensive (NT) individuals. There were no significant differences in overall distri-bution of genotypes or alleles between EH patients and NT subjects. Also, there were no significant differ-ences in the haplotype-based case-control study. The present results do not indicate an association between the t-PA gene and EH.
International Journal of Biomedical Science. 01/2006;
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ABSTRACT: A versatile convergent approach for preparing the pumiliotoxin alkaloids has been developed employing Pd(0)-catalyzed cross-coupling reactions between homoallylic organozincs and vinyl iodides. The (Z)-iodoalkylidene indolizidine 34, which served as a common key intermediate, was synthesized through highly stereoselective addition of the chiral silylallene 19 to (S)-acetylpyrrolidine followed by a palladium-catalyzed intramolecular carbonylation[bond]cyclization sequence. This synthetic process allowed the first total synthesis of (+)-pumiliotoxin 225F. The intermediate (Z)-iodoalkylidene indolizidine 34 obtained was converted to a homoallylzinc chloride derivative and subjected to homoallyl-vinyl cross-coupling with the (E)-vinyl iodide 42 using Pd(PPh(3))(4) catalyst to give the cross-coupled product 47 with a 1,5-diene side chain. Subsequent deprotection provided (+)-pumiliotoxin A. On the other hand, the (Z)-iodoalkylidene indolizidine 34 was transformed into the homoallyl-tert-butyl zinc derivative, which underwent palladium-catalyzed cross-coupling with the (E)-vinyl iodide 50 and subsequent deprotection to afford (+)-pumiliotoxin B.
The Journal of Organic Chemistry 09/2002; 67(16):5517-26. · 4.45 Impact Factor
