matrix metalloproteinase 9

Summary

Summary: An endopeptidase that is structurally similar to MATRIX METALLOPROTEINASE 2. It degrades GELATIN types I and V; COLLAGEN TYPE IV; and COLLAGEN TYPE V.

Top Publications

  1. Hanifeh M, Rajamäki M, Syrjä P, Mäkitalo L, Kilpinen S, Spillmann T. Identification of matrix metalloproteinase-2 and -9 activities within the intestinal mucosa of dogs with chronic enteropathies. Acta Vet Scand. 2018;60:16 pubmed publisher
    ..The results provide supporting evidence for the possible involvement of MMP-2 and -9 in the pathogenesis of canine CE. ..
  2. Xu Y, Chen F, Zhang Y, Zhao Q, Guan X, Wang H, et al. The long noncoding RNA FOXCUT promotes proliferation and migration by targeting FOXC1 in nasopharyngeal carcinoma. Tumour Biol. 2017;39:1010428317706054 pubmed publisher
    ..carcinoma cell lines and resulted in downregulated expression of the matrix metalloproteinase 7 and matrix metalloproteinase 9, as well as vascular endothelial growth factor A and ?-catenin...
  3. Kolho K, Sipponen T, Valtonen E, Savilahti E. Fecal calprotectin, MMP-9, and human beta-defensin-2 levels in pediatric inflammatory bowel disease. Int J Colorectal Dis. 2014;29:43-50 pubmed
    ..Fecal HBD-2 did not bring information to the disease characteristics of pediatric IBD patients. ..
  4. Yamada Y, Matsumoto T. House Dust Mites Induce Production of Endothelin-1 and Matrix Metalloproteinase-9 in Keratinocytes via Proteinase-Activated Receptor-2 Activation. Int Arch Allergy Immunol. 2017;173:84-92 pubmed publisher
    ..These results suggest that the activation of PAR-2 on keratinocytes by HDM-derived serine proteases induces the production of ET-1 and MMP-9, and may contribute to the induction of pruritus in AD. ..
  5. Martinez R, Pinho Ribeiro F, Vale D, Steffen V, Vicentini F, Vignoli J, et al. Trans-chalcone added in topical formulation inhibits skin inflammation and oxidative stress in a model of ultraviolet B radiation skin damage in hairless mice. J Photochem Photobiol B. 2017;171:139-146 pubmed publisher
    ..Therefore, topical treatment with TC is a novel therapeutic approach for the treatment of UVB radiation skin damages, which merits further pre-clinical and clinical investigation. ..
  6. Rajagopalan S, Meng X, Ramasamy S, Harrison D, Galis Z. Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability. J Clin Invest. 1996;98:2572-9 pubmed
    ..Thus, reactive oxygen species can modulate matrix degradation in areas of high oxidant stress and could therefore contribute to instability of atherosclerotic plaques. ..
  7. Shao L, Zhang B, Wang L, Wu L, Kan Q, Fan K. MMP-9-cleaved osteopontin isoform mediates tumor immune escape by inducing expansion of myeloid-derived suppressor cells. Biochem Biophys Res Commun. 2017;493:1478-1484 pubmed publisher
    ..These findings suggest that the MMP-9-cleaved OPN fragment, OPN-32kDa, was responsible for MDSCs expansion, which may contribute to tumor's evasion of the immune response...
  8. Han Y, Kee J, Kim D, Mun J, Park S, Kim Y, et al. Arctii Fructus Inhibits Colorectal Cancer Cell Proliferation and MMPs Mediated Invasion via AMPK. Am J Chin Med. 2017;45:1309-1325 pubmed publisher
    ..Collectively, this study demonstrates that AF inhibits the proliferation and metastatic properties of CRC cells. ..
  9. Chen W, Zhu H, Yin L, Wang T, Wu J, Xu J, et al. lncRNA-PVT1 Facilitates Invasion Through Upregulation of MMP9 in Nonsmall Cell Lung Cancer Cell. DNA Cell Biol. 2017;36:787-793 pubmed publisher
    ..These findings suggest that lncRNA-PVT1 could predispose NSCLC patients to metastases and may serve as a promising target for antimetastatic therapies. ..

More Information

Publications62

  1. Hu J, Liu K, Liu J, Jiang X, Wang X, Chen Y, et al. CD163 as a marker of M2 macrophage, contribute to predicte aggressiveness and prognosis of Kazakh esophageal squamous cell carcinoma. Oncotarget. 2017;8:21526-21538 pubmed publisher
  2. Tang J, Qin Z, Han P, Wang W, Yang C, Xu Z, et al. High Annexin A5 expression promotes tumor progression and poor prognosis in renal cell carcinoma. Int J Oncol. 2017;50:1839-1847 pubmed publisher
    ..Annexin A5 may be a potential prognostic biomarker in RCC and promotes proliferation, migration and invasion of RCC cells via activating PI3K/Akt/mTOR signaling pathway and regulating EMT process and MMP expression. ..
  3. Orlovic M, Tomic V, Vukojevic K, Hudić I, Mandic V, Azinovic I, et al. Decreased expression of MMP-9 in CD8+ cells in placenta with severe preeclampsia. Biotech Histochem. 2017;92:288-296 pubmed publisher
    ..We also evaluated the expression of matrix metalloproteinase 9 (MMP-9) in CD4+ and CD8+ cells...
  4. Guo Y, Zhang Z, Wei H, Wang J, Lv J, Zhang K, et al. Cytotoxic necrotizing factor 1 promotes prostate cancer progression through activating the Cdc42-PAK1 axis. J Pathol. 2017;243:208-219 pubmed publisher
    ..Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. ..
  5. Ying S, Jiang Z, He X, Yu M, Chen R, Chen J, et al. Serum HMGB1 as a Potential Biomarker for Patients with Asbestos-Related Diseases. Dis Markers. 2017;2017:5756102 pubmed publisher
    ..Thus, our study provides supporting evidence for HMGB1 as a potential biomarker either for the clinical diagnosis of high-risk AE cohorts or for evaluating ARDs. ..
  6. Farooq V, Gogas B, Serruys P. Restenosis: delineating the numerous causes of drug-eluting stent restenosis. Circ Cardiovasc Interv. 2011;4:195-205 pubmed publisher
  7. Bruns C, Harbison M, Kuniyasu H, Eue I, Fidler I. In vivo selection and characterization of metastatic variants from human pancreatic adenocarcinoma by using orthotopic implantation in nude mice. Neoplasia. 1999;1:50-62 pubmed
  8. Pirrone F, Pastore C, Mazzola S, Albertini M. In vivo study of the behaviour of matrix metalloproteinases (MMP-2, MMP-9) in mechanical, hypoxic and septic-induced acute lung injury. Vet Res Commun. 2009;33 Suppl 1:121-4 pubmed publisher
  9. Dale M, Fitzgerald M, Liu Z, Meisinger T, Karpisek A, Purcell L, et al. Premature aortic smooth muscle cell differentiation contributes to matrix dysregulation in Marfan Syndrome. PLoS ONE. 2017;12:e0186603 pubmed publisher
    ..This study indicates that an early phenotypic switch appears to be associated with initiation of important metabolic changes in SMCs that contribute to subsequent pathology in MFS. ..
  10. Yu G, Li A, Li X, Yang Z, Peng H. Bispecific antibody suppresses osteosarcoma aggressiveness through regulation of NF-?B signaling pathway. Tumour Biol. 2017;39:1010428317705572 pubmed publisher
    ..In conclusion, these results provided new evidence that BsAbBmi/TRIM inhibited the progression of osteosarcoma, which suggest that BsAbBmi/TRIM may be a novel anti-cancer agent for osteosarcoma therapy. ..
  11. Yan P, Chen K, Wang Q, Yang D, Li D, Yang Y. UCP-2 is involved in angiotensin-II-induced abdominal aortic aneurysm in apolipoprotein E-knockout mice. PLoS ONE. 2017;12:e0179743 pubmed publisher
    ..This study provides a mechanism by which UCP-2, via anti-oxidants and anti-apoptosis, participates in the preventing of AAA formation. ..
  12. Osanai K, Kobayashi Y, Otsu M, Izawa T, Sakai K, Iwashita M. Ramelteon, a selective MT1/MT2 receptor agonist, suppresses the proliferation and invasiveness of endometrial cancer cells. Hum Cell. 2017;30:209-215 pubmed publisher
    ..These results suggested that ramelteon may be a candidate for the treatment of recurrent endometrial cancer, with activity similar to that of melatonin. ..
  13. Zhang J, Deb S, Gottschall P. Regional and differential expression of gelatinases in rat brain after systemic kainic acid or bicuculline administration. Eur J Neurosci. 1998;10:3358-68 pubmed
    ..Although similar in catalytic activity, MMP-9 and MMP-2 may play different roles in response to kainic acid-induced seizure and neuronal degeneration. ..
  14. Jhou B, Song T, Lee I, Hu M, Yang N. Lycopene Inhibits Metastasis of Human Liver Adenocarcinoma SK-Hep-1 Cells by Downregulation of NADPH Oxidase 4 Protein Expression. J Agric Food Chem. 2017;65:6893-6903 pubmed publisher
    ..ng/mL) significantly increased migration, invasion, and adhesion activity, the intracellular ROS level, matrix metalloproteinase 9 (MMP-9) and MMP-2 activities, the level of NOX4 protein expression, and NOX activity...
  15. Ren L, Xu Y, Liu C, Wang S, Qin G. IL-17RB enhances thyroid cancer cell invasion and metastasis via ERK1/2 pathway-mediated MMP-9 expression. Mol Immunol. 2017;90:126-135 pubmed publisher
  16. Liao H, Pan C, Chou P, Chen Y, Wu T, Sheu M, et al. Toxicological effects of NCKU-21, a phenanthrene derivative, on cell growth and migration of A549 and CL1-5 human lung adenocarcinoma cells. PLoS ONE. 2017;12:e0185021 pubmed publisher
  17. Wang Y, Chu Y, Yue B, Ma X, Zhang G, Xiang H, et al. Adipose-derived mesenchymal stem cells promote osteosarcoma proliferation and metastasis by activating the STAT3 pathway. Oncotarget. 2017;8:23803-23816 pubmed publisher
    ..After the siRNA treatment, the MMP2, MMP9 and Ki67 levels decreased. Based on these data, stromal ADSCs promote osteosarcoma progression by increasing STAT3 signalling-mediated MMP2/9 expression. ..
  18. Lu C, Ma J, Cai D. Increased HAGLR expression promotes non-small cell lung cancer proliferation and invasion via enhanced de novo lipogenesis. Tumour Biol. 2017;39:1010428317697574 pubmed publisher
    ..Therefore, targeting HAGLR may be a possible therapeutic strategy for non-small cell lung cancer. ..
  19. Matulewicz N, Stefanowicz M, Nikolajuk A, Karczewska Kupczewska M. Markers of Adipogenesis, but Not Inflammation, in Adipose Tissue Are Independently Related to Insulin Sensitivity. J Clin Endocrinol Metab. 2017;102:3040-3049 pubmed publisher
    ..Macrophages seem to be the first immune cells to infiltrate AT. Adipogenesis and ECM remodeling are the initial processes in AT that are independently associated with insulin sensitivity. ..
  20. Glebauskiene B, Liutkeviciene R, Vilkeviciute A, Kriauciuniene L, Jakstiene S, Zlatkute E, et al. Does MMP-9 Gene Polymorphism Play a Role in Pituitary Adenoma Development?. Dis Markers. 2017;2017:5839528 pubmed publisher
    ..0% versus 71.4%; p < 0.001. Conclusion. MMP-9 (-1562) C/C genotype plays a role in nonrecurrence, inactive, and invasive as well as in nonivasive PA development. ..
  21. Jiang G, Zhang Y, Zhang X, Lin X, Yu J, Wang E. Inversin correlates with the malignant phenotype of non-small cell lung cancer and promotes the invasiveness of lung cancer cells. Tumour Biol. 2017;39:1010428317691177 pubmed publisher
    ..Collectively, these results indicated that inversin might promote the tumorigenicity of lung cancer cells and serve as a novel therapeutic target of non-small cell lung cancer. ..
  22. Gonzalez Cortes T, Recio Vega R, LANTZ R, Chau B. DNA methylation of extracellular matrix remodeling genes in children exposed to arsenic. Toxicol Appl Pharmacol. 2017;329:140-147 pubmed publisher
  23. Rossano R, Larocca M, Riviello L, Coniglio M, Vandooren J, Liuzzi G, et al. Heterogeneity of serum gelatinases MMP-2 and MMP-9 isoforms and charge variants. J Cell Mol Med. 2014;18:242-52 pubmed
    ..These observations open perspectives for better diagnosis and prognosis of many diseases and need to be critically interpreted when applying other methods for MS and other diseases. ..
  24. Mohieldin E, Muddathir A, Mitsunaga T. Inhibitory activities of selected Sudanese medicinal plants on Porphyromonas gingivalis and matrix metalloproteinase-9 and isolation of bioactive compounds from Combretum hartmannianum (Schweinf) bark. BMC Complement Altern Med. 2017;17:224 pubmed publisher
    ..Because of terchebulin and some crude extracts acting on P. gingivalis bacteria and MMP-9 enzyme that would make them promising natural preference for preventing and treating periodontal diseases. ..
  25. Tiveron M, Pomerantzeff P, de Lourdes Higuchi M, Reis M, de Jesus Pereira J, Kawakami J, et al. Infectious agents is a risk factor for myxomatous mitral valve degeneration: A case control study. BMC Infect Dis. 2017;17:297 pubmed publisher
    ..Despite of low percentage of Borrelia burgdorferi in MD group, this agent was correlated with myxomatous degeneration and this may occour due synergistic actions between these infectious agents likely contribute to collagen degradation. ..
  26. Li Q, Yu Q, Na R, Liu B. Etanercept protects rat cardiomyocytes against hypertrophy by regulating inflammatory cytokines secretion and cell apoptosis. Braz J Med Biol Res. 2017;50:e5868 pubmed publisher
    ..05). Etanercept may protect rat cardiomyocytes from hypertrophy by inhibiting inflammatory cytokines secretion and cell apoptosis. ..
  27. Jin H, Xie Q, Guo X, Xu J, Wang A, Li J, et al. p63? protein up-regulates heat shock protein 70 expression via E2F1 transcription factor 1, promoting Wasf3/Wave3/MMP9 signaling and bladder cancer invasion. J Biol Chem. 2017;292:15952-15963 pubmed publisher
  28. Berger R, Pak B, Kolesnikova M, Fromkin J, Saladino R, Herman B, et al. Derivation and Validation of a Serum Biomarker Panel to Identify Infants With Acute Intracranial Hemorrhage. JAMA Pediatr. 2017;171:e170429 pubmed publisher
  29. Zhijun L, Dapeng W, Hong J, Guicong W, Bingjian Y, Honglin L. Overexpression of CPEB4 in glioma indicates a poor prognosis by promoting cell migration and invasion. Tumour Biol. 2017;39:1010428317694538 pubmed publisher
  30. Tan B, Li Y, Fan L, Zhao Q, Liu Q, Liu Y, et al. Upregulated Vav2 in gastric cancer tissues promotes tumor invasion and metastasis. Tumour Biol. 2017;39:1010428317698392 pubmed publisher
    ..We concluded that Vav2 might promote invasion and metastasis of gastric cancer by regulating some invasion and metastasis-related genes. ..
  31. Zhang Q, Zhang Y, Hu X, Qin Y, Zhong W, Meng J, et al. Thymidine phosphorylase promotes metastasis and serves as a marker of poor prognosis in hepatocellular carcinoma. Lab Invest. 2017;97:903-912 pubmed publisher
    ..In addition, MMP2 and MMP9 were activated by TP overexpression. Overall, this study suggests that TP promotes metastasis and may serve as a marker of poor prognosis in HCC. Thus, TP is a potential target for the treatment of HCC. ..
  32. Jiang L, Yan Q, Fang S, Liu M, Yuan Y, Li Y, et al. Calcium-binding protein 39 promotes hepatocellular carcinoma growth and metastasis by activating extracellular signal-regulated kinase signaling pathway. Hepatology. 2017;66:1529-1545 pubmed publisher
    ..Better understanding of CAB39 may lead to its clinical application as a biomarker for a prognosis predictor and a novel therapeutic target. (Hepatology 2017;66:1529-1545). ..
  33. Zhong C, Yang J, Xu T, Xu T, Peng Y, Wang A, et al. Serum matrix metalloproteinase-9 levels and prognosis of acute ischemic stroke. Neurology. 2017;89:805-812 pubmed publisher
    ..004). Higher serum MMP-9 levels in the acute phase of ischemic stroke were associated with increased risk of mortality and major disability, suggesting that serum MMP-9 could be an important prognostic factor for ischemic stroke. ..
  34. Keyvani Ghamsari S, Rabbani Chadegani A, Sargolzaei J, Shahhoseini M. Effect of irinotecan on HMGB1, MMP9 expression, cell cycle, and cell growth in breast cancer (MCF-7) cells. Tumour Biol. 2017;39:1010428317698354 pubmed publisher
  35. Piechota Polanczyk A, Włodarczyk M, Sobolewska Włodarczyk A, Jonakowski M, Pilarczyk A, Stec Michalska K, et al. Serum Cyclophilin A Correlates with Increased Tissue MMP-9 in Patients with Ulcerative Colitis, but Not with Crohn's Disease. Dig Dis Sci. 2017;62:1511-1517 pubmed publisher
    ..Higher CyPA level may be followed by increased MMP-9 in those patients. However, further studies are necessary to verify the role of CyPA in IBD development. ..
  36. Liu W, Yamashita T, Kurata T, Kono S, Hishikawa N, Deguchi K, et al. Protective effect of telmisartan on neurovascular unit and inflammasome in stroke-resistant spontaneously hypertensive rats. Neurol Res. 2015;37:491-501 pubmed publisher
    ..These results suggest that telmisartan comprehensively protected the NVU components by reducing inflammatory reactions relative to AD in hypertensive rats, which could also preclude the risk of AD under hypertension. ..
  37. Kondo A, Nonaka A, Shimamura T, Yamamoto S, Yoshida T, Kodama T, et al. Long Noncoding RNA JHDM1D-AS1 Promotes Tumor Growth by Regulating Angiogenesis in Response to Nutrient Starvation. Mol Cell Biol. 2017;37: pubmed publisher
    ..Our results provide evidence that increased JHDM1D-AS1 expression under nutrient starvation accelerates tumor growth by upregulating angiogenesis, thus laying the foundation for improved therapeutic strategies. ..
  38. Wang Z, He C, Hu L, Shi H, Li J, Gu Q, et al. Long noncoding RNA UCA1 promotes tumour metastasis by inducing GRK2 degradation in gastric cancer. Cancer Lett. 2017;408:10-21 pubmed publisher
    ..Our results suggest that UCA1 might function as a mediator of protein ubiquitination and may be a promising molecular target for GC therapy. ..
  39. Gieger T, Nettifee Osborne J, Hallman B, Johannes C, Clarke D, Nolan M, et al. The impact of carboplatin and toceranib phosphate on serum vascular endothelial growth factor (VEGF) and metalloproteinase-9 (MMP-9) levels and survival in canine osteosarcoma. Can J Vet Res. 2017;81:199-205 pubmed
    ..Bien que ce traitement ait été bien toléré, les temps de survie n’ont pas excédé les résultats publiés antérieurement pour des chiens traités par amputation et chimiothérapie uniquement.(Traduit par Docteur Serge Messier). ..
  40. Mao L, Li P, Zhu W, Cai W, Liu Z, Wang Y, et al. Regulatory T cells ameliorate tissue plasminogen activator-induced brain haemorrhage after stroke. Brain. 2017;140:1914-1931 pubmed publisher
    ..Thus, regulatory T cell adoptive transfer may be useful as a cell-based therapy to improve the efficacy and safety of thrombolytic treatment for ischaemic stroke. ..
  41. Khan H, Singh R, Tiwari R, Gangopadhyay S, Roy S, SINGH D, et al. Mercury exposure induces cytoskeleton disruption and loss of renal function through epigenetic modulation of MMP9 expression. Toxicology. 2017;386:28-39 pubmed publisher
    ..In this study, we have shown for the first time how MeHg could epigenetically modulate matrix metalloproteinase 9(MMP9) to promote nephrotoxicity using an animal model of sub chronic MeHg exposure...
  42. Ellinghaus U, Cortini A, Pinder C, Le Friec G, Kemper C, Vyse T. Dysregulated CD46 shedding interferes with Th1-contraction in systemic lupus erythematosus. Eur J Immunol. 2017;47:1200-1210 pubmed publisher
    ..These data may deliver the first mechanistic explanation for the increased serum CD46 levels observed in SLE patients and indicate that targeting CD46-cleaving proteases could be a novel avenue to modulate Th1 responses. ..
  43. Muscella A, Vetrugno C, Marsigliante S. CCL20 promotes migration and invasiveness of human cancerous breast epithelial cells in primary culture. Mol Carcinog. 2017;56:2461-2473 pubmed publisher
    ..These results reveal a role for CCL20 also in tumor breast cell and point to CCL20 as a novel therapeutic target in cancer. ..
  44. Underwood D, Osborn R, Bochnowicz S, Webb E, Rieman D, Lee J, et al. SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung. Am J Physiol Lung Cell Mol Physiol. 2000;279:L895-902 pubmed
    ..Therefore, SB 239063 demonstrates activity against a range of sequelae commonly associated with COPD and fibrosis, supporting the therapeutic potential of p38 MAPK inhibitors such as SB 239063 in chronic airway disease. ..
  45. Farghali H, AbdElKader N, Khattab M, AbuBakr H. Evaluation of subcutaneous infiltration of autologous platelet-rich plasma on skin-wound healing in dogs. Biosci Rep. 2017;37: pubmed publisher
    ..S/C infiltration of autologous PRP at the wound margins enhances the wound epithelization and reduces the scar tissue formation. ..
  46. Sasaki K, Hattori T, Fujisawa T, Takahashi K, Inoue H, Takigawa M. Nitric oxide mediates interleukin-1-induced gene expression of matrix metalloproteinases and basic fibroblast growth factor in cultured rabbit articular chondrocytes. J Biochem. 1998;123:431-9 pubmed
  47. Zocevic A, Rouillon J, Wong B, Servais L, Voit T, Svinartchouk F. Evaluation of the serum matrix metalloproteinase-9 as a biomarker for monitoring disease progression in Duchenne muscular dystrophy. Neuromuscul Disord. 2015;25:444-6 pubmed publisher
  48. Lin X, Chen L, Yao X. [The impact of different duration of EA-pretreatment on expression of MMP-9 and VEGF in blood-brain barrier in rats with cerebral ischemia-reperfusion injury]. Zhen Ci Yan Jiu. 2015;40:40-4 pubmed
    ..Longer EA-pretreatment is relatively better. ..
  49. Wang P, Li C, Wang X, Xiong W, Feng X, Liu Q, et al. Anti-metastatic and pro-apoptotic effects elicited by combination photodynamic therapy with sonodynamic therapy on breast cancer both in vitro and in vivo. Ultrason Sonochem. 2015;23:116-27 pubmed
    ..In addition, Ce6-mediated SPDT significantly inhibited tumor growth and metastasis in mouse breast cancer 4T1 xenograft model, in which MMP-9 and VEGF may play a crucial role. ..
  50. Toni M, Hermida J, Goñi M, Fernandez P, Parks W, Toledo E, et al. Matrix metalloproteinase-10 plays an active role in microvascular complications in type 1 diabetic patients. Diabetologia. 2013;56:2743-52 pubmed
    ..MMP-10 is involved in the development of microvascular complications in type 1 diabetes and emerges as a potential therapeutic target for slowing down the evolution of diabetic nephropathy and retinopathy. ..
  51. Shim S, Jang H, Myung H, Myung J, Kang J, Kim M, et al. Rebamipide ameliorates radiation-induced intestinal injury in a mouse model. Toxicol Appl Pharmacol. 2017;329:40-47 pubmed publisher
  52. Cho J, Joo Y, Shin E, Park E, Kim M. Anticancer Effects of Colchicine on Hypopharyngeal Cancer. Anticancer Res. 2017;37:6269-6280 pubmed
    ..Colchicine has the potential to prevent disease progression in hypopharyngeal cancer and may have application as an adjunctive treatment...
  53. Shao A, Wu H, Chen S, Ammar A, Zhang J, Hong Y. Resveratrol attenuates early brain injury after subarachnoid hemorrhage through inhibition of NF-?B-dependent inflammatory/MMP-9 pathway. CNS Neurosci Ther. 2014;20:182-5 pubmed publisher