|
1
|
Tamura K, Watanabe K, Matsushita Y, Watanabe H, Motoyama D, Ito T, Sugiyama T, Otsuka A, Miyake H. Enhanced Sensitivity to NVP-BEZ235 by Inhibition of p62/SQSTM1 in Human Bladder Cancer KoTCC-1 Cells Both In Vitro and In Vivo. In Vivo 2021; 34:1001-1008. [PMID: 32354885 DOI: 10.21873/invivo.11868] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 01/20/2020] [Accepted: 01/24/2020] [Indexed: 12/25/2022]
Abstract
BACKGROUND/AIM The prognosis of patients with invasive bladder cancer remains poor. The objective of this study was to evaluate the efficacy of NVP-BEZ235 (NVP), a dual PI3K/mTOR inhibitor, combined with the inactivation of p62/SQSTM1 (p62) in a human bladder cancer KoTCC-1 model. MATERIALS AND METHODS An expression plasmid with short hairpin RNA targeted against p62 was transfected into KoTCC-1 cells (KoTCC-1/sh-p62). The antitumor effects of NVP on KoTCC-1/sh-p62 were investigated in comparison with those on KoTCC-1 transfected with a control plasmid alone (KoTCC-1/C). RESULTS KoTCC-1/sh-p62 showed significantly higher sensitivity to NVP than KoTCC-1/C. Treatment of both cell lines with NVP markedly inactivated the PI3K/Akt/mTOR signaling pathway. However, NVP treatment stimulated the autophagic pathway in KoTCC-1/C, but not in KoTCC-1/sh-p62. Furthermore, compared with KoTCC-1/C, NVP treatment induced apoptosis of KoTCC-1/sh-p62 cells, which was accompanied by significant downregulation of c-IAP-1 and XIAP as well as upregulation of Bax. Moreover, the in vivo growth of KoTCC-1/sh-p62 tumors was significantly suppressed by treatment with NVP compared to KoTCC-1/C tumors. CONCLUSION Inhibition of p62 expression combined with NVP may represent an effective therapeutic approach for patients with invasive bladder cancer.
Collapse
Affiliation(s)
- Keita Tamura
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Kyohei Watanabe
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yuto Matsushita
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hiromitsu Watanabe
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Daisuke Motoyama
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Toshiki Ito
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takayuki Sugiyama
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Atsushi Otsuka
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hideaki Miyake
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| |
Collapse
|
|
2
|
Abstract
Background The aim of the present study was to determine whether the interleukin-6 (IL-6) -572G/C polymorphism correlates with prostate cancer. Methods According to inclusion and exclusion criteria, the association of the IL-6 -572G/C polymorphism with prostate cancer was searched in databases and analyzed using comprehensive meta-analysis software. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the associations. Results We considered a total of six case-control studies including 2237 patients and 1754 controls and the meta-analysis results showed significant association between the IL-6 -572G/C polymorphism and prostate cancer risk(CC vs GG: OR = 0.49, 95% CI =0.37–0.65;CG vs GG: OR =0.71, 95% CI = 0.58–0.87; the dominant model: OR =0.65, 95% CI = 0.54–0.79;the recessive model: OR =0.70, 95% CI = 0.58–0.85). In stratified analyses by ethnicity, significant associations were found among Asian populations. However, no significant association was found in Caucasian populations. Conclusion Our findings demonstrated that the -572G/C polymorphism of the IL-6 gene may be a risk factor for the development of prostate cancer in Asians.
Collapse
Affiliation(s)
- Yingwei Wang
- Clinical laboratory, Tiantai people's hospital, Tiantai, Zhejiang 317200, China
| | - Xin Chen
- Clinical laboratory, Tiantai people's hospital, Tiantai, Zhejiang 317200, China
| | - Yafei Chen
- Clinical laboratory, Tiantai people's hospital, Tiantai, Zhejiang 317200, China
| |
Collapse
|
|
3
|
Nishikawa M, Miyake H, Fujisawa M. Enhanced Sensitivity to Sunitinib by Inhibition of Akt1 Expression in Human Castration-resistant Prostate Cancer PC3 Cells Both In Vitro and In Vivo. Urology 2015; 85:1215.e1-1215.e7. [PMID: 25917740 DOI: 10.1016/j.urology.2015.02.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Revised: 01/27/2015] [Accepted: 02/16/2015] [Indexed: 11/16/2022]
Abstract
OBJECTIVE To investigate whether antitumor activity of sunitinib is enhanced by silencing Akt1 in a human castration-resistant prostate cancer PC3 model. MATERIALS AND METHODS We initially established PC3 in which the expression vector containing a short hairpin ribonucleic acid targeting Akt1 was introduced (PC3/sh-Akt1). Changes in various phenotypes of PC3/sh-Akt1 after treatment with sunitinib were compared with those of PC3 transfected with control vector alone (PC3/C) both in vitro and in vivo. RESULTS When cultured in the standard medium, in vitro growth of PC3/sh-Akt1 was almost similar to that of PC3/C. However, compared with PC3/C, PC3/sh-Akt1 showed a significantly higher sensitivity to sunitinib, accompanying impaired phosphorylation of p44/42 mitogen-activated protein kinase, downregulation of Bcl-2, and upregulation of Bax. In addition, treatment with sunitinib significantly suppressed the migration ability of PC3/sh-Akt1 compared with that of PC3/C. In vivo, administration of sunitinib induced the significantly marked growth inhibition of PC3/sh-Akt1 compared with that of PC3/C, and apoptotic index in PC3/sh-Akt1 tumor in mice treated with sunitinib was significantly greater than that in PC3/C tumor. CONCLUSION Combined treatment with Akt1 inhibitor and sunitinib could be a promising therapeutic approach for men with castration-resistant prostate cancer.
Collapse
Affiliation(s)
- Masatomo Nishikawa
- Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hideaki Miyake
- Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan.
| | - Masato Fujisawa
- Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
| |
Collapse
|
|
4
|
Characterization of mechanism involved in acquired resistance to sorafenib in a mouse renal cell cancer RenCa model. Clin Transl Oncol 2013; 16:801-6. [DOI: 10.1007/s12094-013-1151-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Accepted: 12/11/2013] [Indexed: 12/28/2022]
|
|
5
|
Kumano M, Miyake H, Abolghait SK, Behnsawy HM, Fujisawa M. β4-integrin-mediated cytotoxic activity of AexU in human prostate cancer PC3 cells. Oncol Lett 2013; 6:1482-1486. [PMID: 24179545 PMCID: PMC3813740 DOI: 10.3892/ol.2013.1542] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Accepted: 08/02/2013] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to characterize the cytotoxic activity of AexU, an effector-mediating type three secretion system (TTSS) of gram-negative bacteria, in human prostate cancer cells, focusing on the association with β4-integrin expression. The cytotoxic effects of AexU either alone or in combination with chemotherapeutic agents were evaluated using several human prostate cancer cell lines. Human prostate cancer PC3 cells, in which an expression vector containing siRNA targeting β4-integrin had been introduced, were established (PC3/sh-In), and the cytotoxic effects of AexU on the PC3/sh-In cells were compared with the PC3 cells that were transfected with a control vector (PC3/C). The expression levels of β4-integrin in the PC3 cells were markedly higher compared with those in the LNCaP or DU145 cells, and the cytotoxic effects of AexU in the PC3 cells were more pronounced compared with those in the LNCaP or DU145 cells. The sensitivity of the PC3 cells to docetaxel and cisplatin was significantly enhanced following treatment with AexU, resulting in a decrease in the IC50 of the two agents by ~90%. The cytotoxic effect of AexU in the PC3/C cells was more marked compared with that in the PC3/sh-In cells, and the phosphorylation of Akt in the PC3/C cells appeared to be significantly more inhibited by the treatment with AexU compared with the PC3/sh-In cells. In conclusion, treatment with AexU may be a useful therapeutic option for prostate cancer when β4-integrin is overexpressed. The treatment appears to exert its effects through growth inhibition and by enhancing the sensitivity of the cancer cells to chemotherapeutic agents.
Collapse
Affiliation(s)
- Masafumi Kumano
- Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
| | | | | | | | | |
Collapse
|
|
6
|
Acquired resistance to temsirolimus in human renal cell carcinoma cells is mediated by the constitutive activation of signal transduction pathways through mTORC2. Br J Cancer 2013; 109:2389-95. [PMID: 24091619 PMCID: PMC3817337 DOI: 10.1038/bjc.2013.602] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 08/10/2013] [Accepted: 09/11/2013] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND The objective of this study was to characterise the mechanism underlying acquired resistance to temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR), in renal cell carcinoma (RCC). METHODS A parental human RCC cell line, ACHN (ACHN/P), was continuously exposed to increasing doses of up to 20 μM of temsirolimus, and a cell line resistant to temsirolimus (ACHN/R), showing a sixfold higher IC50 than that of ACHN/P, was developed. RESULTS Following treatment with temsirolimus, phosphorylation of S6 kinase in ACHN/P was markedly inhibited, whereas there was no detectable expression of phosphorylated S6 in ACHN/R before and after temsirolimus treatment. However, AKT and p44/42 mitogen-activated protein kinase (MAPK) were constitutively phosphorylated even after temsirolimus treatment in ACHN/R, but not in ACHN/P. There was no significant difference between the sensitivities of ACHN/P and ACHN/R to KU0063794, a dual inhibitor of mTOR complex 1 (mTORC1) and mTORC2. Similar sensitivities to temsirolimus in ACHN/P and ACHN/R could be achieved by additional treatment with specific inhibitors of AKT- and MAPK-signaling pathways. CONCLUSION The activation of signal transduction pathways via mTORC2, but not via mTORC1, may have an important role in the acquisition of a resistant phenotype to temsirolimus in RCC.
Collapse
|
|
7
|
Sakai I, Miyake H, Fujisawa M. Acquired resistance to sunitinib in human renal cell carcinoma cells is mediated by constitutive activation of signal transduction pathways associated with tumour cell proliferation. BJU Int 2013; 112:E211-20. [PMID: 23305097 DOI: 10.1111/j.1464-410x.2012.11655.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
UNLABELLED WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Although there have been a few studies investigating the molecular mechanism mediating the acquisition of resistance to molecular-targeted agents, including sunitinib, by renal cell carcinoma (RCC) cells, this mechanism remains largely unclear. The maintenance of protein kinase activation during sunitinib treatment may be involved in the acquisition of a phenotype resistant to sunitinib in RCC, and additional treatment with agents targeting activated protein kinases could be a promising approach for overcoming resistance to sunitinib in RCC. OBJECTIVE To characterise the mechanism involved in the acquired resistance to sunitinib, a potential inhibitor of multiple receptor tyrosine kinases (RTKs), in renal cell carcinoma (RCC). MATERIALS AND METHODS A parental human RCC cell line, ACHN (ACHN/P), was continuously exposed to increasing doses of sunitinib, and a cell line resistant to sunitinib (ACHN/R), showing an ≈5-fold higher IC50 (concentration that reduces the effect by 50%) than that of ACHN/P, was developed. RESULTS ACHN/R appeared to acquire significant cross resistance to sorafenib; however, there were no significant differences in sensitivities to the Mammalian target of rapamycin inhibitors, temsirolimus and everolimus, between ACHN/P and ACHN/R. After sunitinib treatment, the expression levels of phosphorylated Akt and p44/42 mitogen-activated protein kinase in ACHN/P, but not those in ACHN/R, were significantly inhibited. RTK assay showed that treatment of ACHN/P with sunitinib resulted in the marked downregulation of several phosphorylated RTKs compared with that of ACHN/R. Additional treatment with a specific inhibitor of Akt significantly increased the sensitivity of ACHN/R to sunitinib, but not that of ACHN/P. There were no significant differences between in vivo growth patterns of ACHN/P and ACHN/R in mice before and after the administration of sunitinib; however, the proportion of cells positive for TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) staining in ACHN/P tumour was significantly greater than that in ACHN/R tumour in mice treated with sunitinib. CONCLUSION The maintenance of protein kinase activation during sunitinib treatment may be involved in the acquisition of resistant phenotype to sunitinib in RCC cells.
Collapse
Affiliation(s)
- Iori Sakai
- Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
| | | | | |
Collapse
|
|
8
|
Interleukin-6 gene -174G>C and -636G>C promoter polymorphisms and prostate cancer risk. Mol Biol Rep 2012; 40:449-55. [PMID: 23073774 DOI: 10.1007/s11033-012-2079-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Accepted: 10/03/2012] [Indexed: 12/14/2022]
Abstract
Prostate cancer (PCa) is one of the most commonly diagnosed internal malignancies affecting men. Due to the important roles of IL-6 in different physiological and pathophysiological processes, IL-6 polymorphisms may modulate PCa risk. IL-6 -174 G>C (rs 1800795, also designated -236 G>C) and -636 G>C (rs 1800796, also designated -572 G>C) promoter polymorphisms have been implicated in PCa susceptibility, albeit still controversial. A literature search using PubMed and Highwire databases was conducted, resulting in eight case-control studies concerning the IL-6 -174 G>C polymorphism (11,613 PCa cases and 13,992 controls) and four case-control publications regarding the IL-6 -636 G>C polymorphism (1,941 PCa cases and 3,357 controls). In order to derive a more precise estimation, a meta-analysis based upon these selected case-control studies was performed. There was no significant association between IL-6 -174 G>C polymorphism and PCa increased risk. Nevertheless, the presence of allele C and the CC genotype were statistically significantly associated with decreased PCa risk in the overall analysis for IL-6 -636 G>C polymorphism. Additional studies in larger samples and analyses of functional repercussions of these SNPs in prostate tumor cells are necessary to validate these findings.
Collapse
|
|
9
|
Salman H, Ori Y, Bergman M, Djaldetti M, Bessler H. Human prostate cancer cells induce inflammatory cytokine secretion by peripheral blood mononuclear cells. Biomed Pharmacother 2012; 66:330-3. [DOI: 10.1016/j.biopha.2012.03.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2012] [Accepted: 03/01/2012] [Indexed: 01/21/2023] Open
|
|
10
|
Wang Y, Li L, Guo X, Jin X, Sun W, Zhang X, Xu RC. Interleukin-6 signaling regulates anchorage-independent growth, proliferation, adhesion and invasion in human ovarian cancer cells. Cytokine 2012; 59:228-36. [PMID: 22595649 DOI: 10.1016/j.cyto.2012.04.020] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2010] [Revised: 04/06/2012] [Accepted: 04/17/2012] [Indexed: 11/30/2022]
Abstract
It has been widely reported that Interleukin-6 (IL-6) is overexpressed in the serum and ascites of ovarian cancer (OVCA) patients, and elevated IL-6 level correlates with poor prognosis and survival. However, the exact role that IL-6 plays in this malignancy or whether IL-6 can regulate tumorigenic properties has not been established. Here we demonstrate that overexpression of IL-6 in non-IL-6-expressing A2780 cells (by transfecting with plasmid encoding for sense IL-6) increases anchorage-independent growth, proliferation, adhesion and invasion, while depletion of endogenous IL-6 expression in IL-6-overexpressing SKOV-3 cells (by transfecting with plasmid encoding for antisense IL-6) decreases. Further investigation indicates that IL-6 promotes OVCA cell proliferation by altering cell cycle distribution rather than inhibiting apoptosis and that IL-6-enhanced OVCA cell invasive may be associated with increased matrix metalloproteinase (MMP)-9 but not MMP-2 proteolytic activity. In addition, overexpressing or deleting of IL-6 in OVCA cells enhances or reduces its receptor (IL-6Rα and gp130) expression and basal phosphorylation levels of both ERK and Akt, and additional treatment with specific inhibitor of the ERK or Akt signaling pathway significantly inhibits the proliferation of IL-6-overexpressing A2780 cells. Our data suggest that the autocrine production of IL-6 by OVCA cells regulates tumorigenic properties of these cells by inducing IL-6 signaling pathways. Thus, regulation of IL-6 expression or its related signaling pathway may be a promising strategy for controlling the progression of OVCA.
Collapse
Affiliation(s)
- Yue Wang
- Department of Immunology, Logistics College of Chinese People's Armed Police Forces, Tianjin, China.
| | | | | | | | | | | | | |
Collapse
|
|
11
|
Azevedo A, Cunha V, Teixeira AL, Medeiros R. IL-6/IL-6R as a potential key signaling pathway in prostate cancer development. World J Clin Oncol 2011; 2:384-96. [PMID: 22171281 PMCID: PMC3235657 DOI: 10.5306/wjco.v2.i12.384] [Citation(s) in RCA: 92] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Revised: 11/08/2011] [Accepted: 11/15/2011] [Indexed: 02/06/2023] Open
Abstract
Interleukin-6 (IL-6) is a pleiotropic cytokine involved in prostate regulation and in prostate cancer (PC) development/progression. IL-6 acts as a paracrine and autocrine growth stimulator in benign and tumor prostate cells. The levels of IL-6 and respective receptors are increased during prostate carcinogenesis and tumor progression. Several studies reported that increased serum and plasma IL-6 and soluble interleukin-6 receptor levels are associated with aggressiveness of the disease and are associated with a poor prognosis in PC patients. In PC treatment, patients diagnosed with advanced stages are frequently submitted to hormonal castration, although most patients will eventually fail this therapy and die from recurrent castration-resistant prostate cancer (CRPC). Therefore, it is important to understand the mechanisms involved in CRPC. Several pathways have been proposed to be involved in CRPC development, and their understanding will improve the way to more effective therapies. In fact, the prostate is known to be dependent, not exclusively, on androgens, but also on growth factors and cytokines. The signaling pathway mediated by IL-6 may be an alternative pathway in the CRPC phenotype acquisition and cancer progression, under androgen deprivation conditions. The principal goal of this review is to evaluate the role of IL-6 pathway signaling in human PC development and progression and discuss the interaction of this pathway with the androgen recepto pathway. Furthermore, we intend to evaluate the inclusion of IL-6 and its receptor levels as a putative new class of tumor biomarkers.The IL-6/IL-6R signaling pathway may be included as a putative molecular marker for aggressiveness in PC and it may be able to maintain tumor growth through the AR pathway under androgen-deprivation conditions. The importance of the IL-6/IL-6R pathway in regulation of PC cells makes it a good candidate for targeted therapy.
Collapse
Affiliation(s)
- Andreia Azevedo
- Andreia Azevedo, Virginia Cunha, Ana Luisa Teixeira, Rui Medeiros, Molecular Oncology and Virology, Portuguese Institute of Oncology, 4200-072 Porto, Portugal
| | | | | | | |
Collapse
|
|
12
|
Sakai I, Miyake H, Terakawa T, Fujisawa M. Inhibition of tumor growth and sensitization to chemotherapy by RNA interference targeting interleukin-6 in the androgen-independent human prostate cancer PC3 model. Cancer Sci 2011; 102:769-75. [PMID: 21214673 DOI: 10.1111/j.1349-7006.2011.01854.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
The objective of the present study was to investigate the inhibitory effects of interleukin-6 (IL-6) secretion by androgen-independent human prostate cancer PC3 cells on their growth and chemosensitivity. In this study, we established PC3 in which the expression vector containing short hairpin RNA (shRNA) targeting IL-6 was introduced (PC3/sh-IL6). Changes in the growth and sensitivity to docetaxel in PC3/sh-IL6 were compared with those in PC3 transfected with control vector alone (PC3/Co). Concentration of IL-6 in the culture supernatant from PC3/sh-IL6 was approximately 20% of that from PC3/Co. Both in vitro and in vivo, the growth of PC3/sh-IL-6 was significantly inferior to that of PC3/Co, accompanying downregulation of Bcl-2, Bcl-xL, phosphorylated Akt, p44/42 mitogen-activated protein kinase, and signal transducers and activation of transcription 3 in PC3/sh-IL-6 compared with that in PC3/Co. Despite the higher sensitivity of PC3/sh-IL6 to docetaxel than that of PC3/Co, the secretion of IL-6 by both cell lines was increased after treatment with docetaxel due to the formation of positive autocrine loops between these cell lines and NFκB signaling pathways. Furthermore, combined treatment with the proteasome inhibitor bortezomib, which completely inhibited the docetaxel-induced IL-6 secretion via the inactivation of NFκB signaling, resulted in the marked sensitization of these cell lines to docetaxel both in vitro and in vivo. These findings suggest that suppressed IL-6 secretion using shRNA, either alone or in combination with docetaxel and bortezomib, could be a useful therapeutic strategy against androgen-independent prostate cancer.
Collapse
Affiliation(s)
- Iori Sakai
- Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
| | | | | | | |
Collapse
|
|
13
|
Current World Literature. Curr Opin Support Palliat Care 2010; 4:207-27. [DOI: 10.1097/spc.0b013e32833e8160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|