Startseite NF2 inhibits proliferation and cancer stemness in breast cancer
Artikel Open Access

NF2 inhibits proliferation and cancer stemness in breast cancer

  • Zhibao Wang , Zhiqiang Zhou EMAIL logo , Zhe Wang und Yijie Cui
Veröffentlicht/Copyright: 17. April 2020
Artikel downloaden (PDF)
Open Medicine
Aus der Zeitschrift Open Medicine Band 15 Heft 1

Abstract

Background

Previous studies have shown that NF2 plays a key role in tumorigenesis. NF2 has been illustrated to be downregulated in several types of human cancer. However, the role of NF2 in breast cancer remains unclear.

Methods

We used UALCAN and KM-plotter database to study NF2 expression in human breast cancer and corresponding normal tissues and analyzed its relationship with clinicopathological parameters. We investigated the role of NF2 in breast cancer cells behavior by inhibiting its expression in MDA-MB-231 and MCF-7 cells.

Results

In this study, we found that NF2 was downregulated in breast cancer tissues compared to the adjacent normal tissues. We found that the low expression of NF2 was related with the tumor stage. NF2 overexpression inhibited the cell colon formation and stemness.

Conclusion

Our results indicate a role of NF2 in the progression of breast cancer.

Keywords: NF2; breast cancer; stemness; proliferation

1 Introduction

Breast cancer is one of the most common cancers in the world [1]. Although the early onset of breast cancer can be effectively treated, the prognosis of patients with recurrent or distant metastatic breast cancer is poor [2]. Therefore, identifying proteins involved in breast tumorigenesis is very important and can be used as a target for therapeutic or diagnostic strategies.

The NF2 gene has two transcripts of NF2-1 and -2, which are composed of exons 1-15 and 17, and exons 1-15 and 16 respectively. The NF2-1 transcript contains 595 amino acid residues and NF2-2 transcript contains 590 amino acid residues [3]. Sherman et al reported that NF2-17 can prevent the growth of murine schwannoma cells in vitro and in vivo, but NF2-16 does not, so it appears as a tumor suppressor [4]. NF2-17 and NF2-16 are expressed in all tissues and many tumors. Mutations in the NF2 gene can simultaneously affect the transcription of the NF2-1 and NF2-2 subtypes [5]. Studies have shown that the NF2 amino acid sequence is highly homologous to the ERM family proteins, and is collectively referred to as MERM [6]. NF2 consists of three domains, the N-terminal functional region, also known as the FERM domain, which is a highly conserved region of the ERM family [7]. NF2 lacks the actin-binding domain in the ERM protein structure. Both NF2 and ERM proteins are connected to muscle in polarized cells [8]. However, the obvious difference between NF2 and other members of ERM is that it can inhibit tumor growth.

The classical NF2 protein is characterized by benign tumors of the nervous system, and its hallmark symptoms include bilateral vestibular schwannomas, meningioma, and ependymoma [9]. NF2 protein regulates contact-dependent growth inhibition by a signal transduction pathway that controls cell proliferation and survival. The NF2 protein is also a cytoskeleton between the molecular scaffold receptor and cortical actin across the membrane, thereby regulating cell adhesion and migration [10].

Studies have shown that NF2 is a novel tumor suppressor protein, and mutation or loss of expression of NF2 protein leads to tumorigenesis, although its molecular mechanism is not fully understood. Overexpression of NF2 prevents cell proliferation and inhibits oncogene-induced transformation. McClatchey et al. reported that NF2 inhibits proliferation of mitotic signaling and contact-dependent inhibition [11]. Shaw et al. observed that pal active kinase 1 (PAK1) promotes the Cyclin D1 promoter activity, but NF2 inhibits PAK1 activation and prevents Rac from binding and activating PAK1 down-regulated Cyclin D1 expression and inhibiting cell growth [12]. NF2 damages the inhibition effect of proto-oncogene MDM2 on p53 and synergizes with p53 to inhibit tumorigenesis. The 130 amino acid residues at the N-terminus of NF2 may play an important role in the degradation of MDM2, and also increase the transcriptional activity dependent on p53 [13].

However, the expression level and function of NF2 in breast cancer remain unclear. In this study, we found that the expression of NF2 in breast cancer tissues was positively correlated with the tumor prognosis. NF2 over-expression can inhibite the cell colon formation and stemness

2 Methods

2.1 Cells and reagents

The breast cancer cell lines MDA-MB-231 and MCF-7 were purchased from the American Type Culture Collection (Manassas, VA, USA). Cell lines were cultured in DMEM medium containing 10% fetal bovine serum (Gibco, USA). All cells were incubated at 37°C in a 5% CO2 incubator.

2.2 Western blot analysis

To prepare protein extracts, MDA-MB-231 and MCF-7 cells were scraped on the ice, collected by centrifugation (1,2000 x g, 10 min, 4˚C) and incubated with freshly prepared RIPA lysis for 15 min. After centrifugation, the concentration of the protein sample is determined by BCA kit. The protein sample is mixed with the loading buffer and boiled for 8 minutes. After that, the sample was separated by a 10% SDS-PAGE gel and electrotransfered to PVDF membrane. The membrane was blocked in 5% skimmed milk. Subsequently, the membrane was incubated with primary antibodies overnight at 4˚C, followed by secondary antibody. Protein bands were visualized using the ECL prime™ blotting system (GE Healthcare, Little Chalfont, UK).

2.3 Proliferation assay

Digestion Cells were harvested on the second day of transfection and inoculated into 96-well plates at a density of 5000 cells/well in triplicate. Subsequently, cultivation for 0, 1, 2, 3 or 4 days, cells were subjected to the CCK8 assay. Briefly, after adding 10μl CCK8 solution to each well, the plate was incubated at 37°C for 4 hours. The absorbance of each well at 595 nm was determined using a microplate reader. The experiment was repeated 3 times.

2.4 Colony formation assay

The cells were harvested the next day after transfection. The cells were seeded at a density of 500 cells/well onto six well plates and colonies were formed within 15 days. The cell colonies were fixed in 4% paraformaldehyde and stained with crystal violet. Colonies were counted using a microscope (> 50 cells) directly on the plate. The experiment was repeated 3 times.

2.5 Colony formation in soft agarose

For the soft agar colony formation assay, cells were seeded at 0.35% top agarose (Promega) at a density of 500 cells per well, and a 0.7% agarose base was added and complete medium was added. The culture was incubated for 3 wk at 37°C in a humidified incubator. The cells were then stained with 0.5 mL of 0.0005% crystal violet and the colonies were visually counted. All experiments were performed in triplicate.

2.6 Cell sphere formation

500 cells were plated in 6-well ultralow attachment plates (3471, Corning) with serum-free medium with 50 ng/ml epidermal growth factor (EGF) (236-EG-200, R&D), 20 ng/ml of basic fibroblast growth factor (bFGF) (233-FB-025, R&D), 1% N2 (17502048, Gibco), 2% B27 (12587-010, Gibco). Then, spheres of diameter greater than 100 μm in each well were counted under a microscope after 10 days.

3 Results

3.1 Protein expression of NF2 in breast cancer

We performed an analysis about NF2 expression in breast cancer tissues by using UALCAN database (http://ualcan.path.uab.edu) Statistical analysis in the UALCAN database revealed that NF2 was down-expressed in breast cancer compared with the normal group, and the difference was statistically significant (P<0.05), as shown in Figure 1.A. Further analysis found that expression of NF2 was lower in breast cancer based on individual cancer stages than normal tissues, and the difference was statistically significant (P<0.05), as shown in Figure 1.B. To further clarify the relationship between NF2 expression level and cancer, pan-cancer analysis revealed that NF2 has lower expression level in cancer tissue compared with normal tissue, as shown in Figure 1.C.

Figure 1 A Protein expression of NF2 in breast cancer. B Protein expression of NF2 in breast cancer based on individual cancer stages. C Pan-cancer view of NF2 expression level.
Figure 1

A Protein expression of NF2 in breast cancer. B Protein expression of NF2 in breast cancer based on individual cancer stages. C Pan-cancer view of NF2 expression level.

3.2 NF2 is correlated with prognosis

We analyzed NF2 mRNA expression in breast cancer tissue by using TCGA database. The statistical analysis shows that NF2 mRNA was downregulated in breast cancer (Figure 2. A). To further clarify the relationship between NF2 expression level and the prognosis of patients with breast cancer, the KM Plotter database analysis was used to show two survival curves of patients with high CD276 expression and low expression group (different probe), and ir was found that CD276 expression level has a significant impact on survival without distant metastasis and recurrence-free survival of patients (Figure 2.B, D). However, for overall survival, that has no significant statistical difference (Figure 2.C).

Figure 2 A NF2 mRNA is down-regulated in breast cancer tissues compared to normal tissues in TCGA cohort, analyzed with the Gene Expression Profiling Interactive Analysis (GEPIA). B Relationship between NF2 expression level and distance metastasis free survival of patients with breast cancer. C Relationship between NF2 expression level and overall survival of patients with breast cancer. D Relationship between NF2 expression level and relapse free survival of patients with breast cancer.
Figure 2

A NF2 mRNA is down-regulated in breast cancer tissues compared to normal tissues in TCGA cohort, analyzed with the Gene Expression Profiling Interactive Analysis (GEPIA). B Relationship between NF2 expression level and distance metastasis free survival of patients with breast cancer. C Relationship between NF2 expression level and overall survival of patients with breast cancer. D Relationship between NF2 expression level and relapse free survival of patients with breast cancer.

3.3 NF2 inhibits cell colony formation

We transfected pcDNA3.1-NF2 plasmid into breast cells. We performed a colony formation assay to detect cell proliferation. Compared to the negative control group, over-expression of NF2 obviously suppressed cell proliferation in MDA-MB-231 cells (Figure 3. A and B). We performed colony formation ability in soft agarose. The results showed overexpression of NF2 reduced colony numbers in A549 cells (Figure 3. C and D).

Figure 3 A Western blot analysis of the overexpression of NF2 in MDA-MB-231 cells (up). Clone formation rate of scramble and NF2 vector transfected MDA-MB-231 cells (down). B Representative images of MDA-MB-231 cell colonies in the colony formation assay. C Western blot analysis of the overexpression of NF2 in MCF-7 cells (up). Clone formation rate of scramble and NF2 vector transfected MCF-7 cells (down). D Representative images of MCF-7 cell colonies in the colony formation assay.
Figure 3

A Western blot analysis of the overexpression of NF2 in MDA-MB-231 cells (up). Clone formation rate of scramble and NF2 vector transfected MDA-MB-231 cells (down). B Representative images of MDA-MB-231 cell colonies in the colony formation assay. C Western blot analysis of the overexpression of NF2 in MCF-7 cells (up). Clone formation rate of scramble and NF2 vector transfected MCF-7 cells (down). D Representative images of MCF-7 cell colonies in the colony formation assay.

3.4 NF2 inhibits cell proliferation and stemness

To explore the impact of NF2 on breast cancer cell proliferation, we performed a CCK8 assay. As shown in Figure 4. A and B, NF2-overexpressed MDA-MB-231 and MCF-7 cells showed weaker proliferation ability compared to negative control siRNA-transfected cells (P < 0.05). The cell sphere assay showed that the overexpression of NF2 suppressed significantly the stemness of MDA-MB-231 and MCF-7 cells (Figure 4.C and D).

Figure 4 A Proliferation curves of scramble and NF2 vector transfected MDA-MB-231 cells. B Proliferation curves of scramble and NF2 vector transfected MCF-7 cells. C Representative images of in vitro sphere-formation assay of NF2 overexpression in MDA-MB-231 cell and control cell. D Representative images of in vitro sphere-formation assay of NF2 overexpression in MCF-7 cell and control cell.
Figure 4

A Proliferation curves of scramble and NF2 vector transfected MDA-MB-231 cells. B Proliferation curves of scramble and NF2 vector transfected MCF-7 cells. C Representative images of in vitro sphere-formation assay of NF2 overexpression in MDA-MB-231 cell and control cell. D Representative images of in vitro sphere-formation assay of NF2 overexpression in MCF-7 cell and control cell.

4 Discussion

At present, there are many studies on NF2 protein in nervous system tumors. Rving et al found that NF2 gene mutations are mostly small fragment gene deletion or insertion, allelic loss, missense mutation, nonsense mutation, etc. Complete deletion of exon 4 is also a common type of mutation [14]. Buceoliero et al observed that the expression of NF2 gene in grade I and II dural sarcoma was higher than that of all dural sarcoma, while the expression of grade III dural sarcoma was lower than the mean [15]. However, inactivation or mutation of the neurofibrin 2 gene (NF2) has not attracted attention in cancer, because they are not common in common human malignancies. But, if they exist, they can affect disease progression, aggressiveness and prognosis. For example, in prostate cancer, inactivation of NF2 is associated with increased invasiveness and chemoresistance [16, 17].

Hiro-kawa et al. found that NF2 directly inhibits the Rac/CDC42-dependent silk/threonine kinase PAK1, which is essential for Ras transformation and NF1 [18]. The mutated NF2 lacks 78 amino acids in the PAK1 inhibitory region and does not inhibit Ras transformation. PAK1-specific inhibitors CEP-1347 and WR-PAK18 selectively inhibited NF2-deficient tumor cells and did not contribute to NF2-positive tumor cells [18]. It indicates that PAK1 is essential for the malignant growth of NF2-deficient cells, and the preventive drug of PAK1 may become a frontier treatment for NF2. These studies suggest that NF2 is closely related to the treatment of tumors.

The NF2 gene is involved in a variety of human tumors and may be a tumor suppressor gene, but its function and mechanism of action are not well understood. An in-depth study of the role of merlin in tumors and its relationship with various signaling molecules and signal transduction pathways may provide an effective biological target for anti-tumor therapy. Activation of NF2 expression may promote tumor cell apoptosis, inhibit tumor growth and metastasis. The use of RNA interference technology to increase NF2 expression may be the goal of treating tumors. However, recent studies suggest that NF2 may also be an oncoprotein. NF2 is expressed differently in different tumors and may be organ specific.

In summary, we investigated the role of NF2 in breast cancer cell stemness, proliferation. Our findings suggest that NF2 may be novel targets for breast cancer therapeutics.

Disclosure

No authors report any conflict of interest.

Reference

[1] Desantis CE, Ma J, Gaudet MM, Newman LA, Miller KD, Sauer AG, et al. Breast cancer statistics, 2019. CA: A Cancer Journal for Clinicians. 2019;69(suppl 12):7-3410.3322/caac.21583Suche in Google Scholar

[2] Badawy M, Abosheisha DM. The diagnostic value of PET/CT in recurrence and distant metastasis in breast cancer patients and impact on disease free survival. Egyptian Journal of Radiology & Nuclear Medicine. 2014;45(4):1317-132410.1016/j.ejrnm.2014.07.006Suche in Google Scholar

[3] Ahronowitz I, Xin W, Kiely R, Sims K, Maccollin M, Nunes FP. Mutational spectrum of the NF2 gene: a meta-analysis of 12 years of research and diagnostic laboratory findings. Human Mutation. 2010;28(1):1-1210.1002/humu.20393Suche in Google Scholar

[4] Sherman L, Xu HM, Geist RT, Saporito-Irwin S, Howells N, Ponta H, et al. Interdomain binding mediates tumor growth suppression by the NF2 gene product. Oncogene. 1997;15(20):2505-250910.1038/sj.onc.1201418Suche in Google Scholar

[5] Uhlmann EJ, Gutmann DH. Tumor suppressor gene regulation of cell growth. Cell Biochemistry & Biophysics. 2001;34(1):6110.1385/CBB:34:1:61Suche in Google Scholar

[6] Chen Z, Fadiel A, Xia Y. Functional duality of merlin: a conundrum of proteome complexity. Medical Hypotheses. 2006;67(5):1095-109810.1016/j.mehy.2006.04.063Suche in Google Scholar PubMed

[7] Melendezvasquez CV, Rios JC, Zanazzi G, Lambert S, Bretscher A, Salzer JL. Nodes of Ranvier form in association with ezrin-radixin-moesin (ERM)-positive Schwann cell processes. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(3):1235-124010.1073/pnas.98.3.1235Suche in Google Scholar PubMed PubMed Central

[8] Maria-Magdalena G, Mobley BC, Orr BA, Shang P, Lehman NL, Zhu X, et al. NHERF1/EBP50 and NF2 as diagnostic markers for choroid plexus tumors. Acta Neuropathologica Communications. 2016;4(1):1-1010.1186/s40478-016-0329-0Suche in Google Scholar

[9] Rebecca Dunbar S, Angelo LS, Razelle K. NF2/merlin in hereditary neurofibromatosis 2 versus cancer: biologic mechanisms and clinical associations. Oncotarget. 2014;5(1):6710.18632/oncotarget.1557Suche in Google Scholar PubMed PubMed Central

[10] Curto M, Mcclatchey AI. Nf2|[sol]|Merlin: a coordinator of receptor signalling and intercellular contact. British Journal of Cancer. 2008;98(2):256-26210.1038/sj.bjc.6604002Suche in Google Scholar PubMed PubMed Central

[11] Cooper J, Xu Q, Zhou L, Pavlovic M, Ojeda V, Moulick K, et al. Combined Inhibition of NEDD8-Activating Enzyme and mTOR Suppresses NF2 Loss-Driven Tumorigenesis. Molecular Cancer Therapeutics. 2017;16(8):169310.1158/1535-7163.MCT-16-0821Suche in Google Scholar PubMed PubMed Central

[12] Kissil JL, Wilker EW, Johnson KC, Eckman MS, Yaffe MB, Jacks T. Merlin, the product of the Nf2 tumor suppressor gene, is an inhibitor of the p21-activated kinase, Pak1. Molecular Cell. 2003;12(4):841-84910.1016/S1097-2765(03)00382-4Suche in Google Scholar

[13] Kim H, Kwak NJ, Lee JY, Choi BH, Lim Y, Ko YJ, et al. Merlin neutralizes the inhibitory effect of Mdm2 on p53. Journal of Biological Chemistry. 2004;279(9):781210.1074/jbc.M305526200Suche in Google Scholar PubMed

[14] Irving RM, Moffat DA, Hardy DG, Barton DE, Xuereb JH, Maher ER. Somatic NF2 gene mutations in familial and non-familial vestibular schwannoma. Human Molecular Genetics. 1994;3(2):347-35010.1093/hmg/3.2.347Suche in Google Scholar PubMed

[15] Buccoliero AM, Castiglione F, D RDI, Gheri CF, Garbini F, Taddei A, et al. NF2 gene expression in sporadic meningiomas: relation to grades or histotypes real time-pCR study. Neuropathology Official Journal of the Japanese Society of Neuropathology. 2010;27(1):36-4210.1111/j.1440-1789.2006.00737.xSuche in Google Scholar PubMed

[16] Kawana Y, Ichikawa T, Suzuki H, Ueda T, Komiya A, Ichikawa Y, et al. Loss of heterozygosity at 7q31.1 and 12p13-12 in advanced prostate cancer. Prostate. 2002;53(1):60-6410.1002/pros.10131Suche in Google Scholar PubMed

[17] Malhotra A, Shibata Y, Hall IM, Dutta A. Chromosomal structural variations during progression of a prostate epithelial cell line to a malignant metastatic state inactivate the NF2, NIPSNAP1, UGT2B17, and LPIN2 genes. Cancer Biology & Therapy. 2013;14(9):840-85210.4161/cbt.25329Suche in Google Scholar PubMed PubMed Central

[18] Hirokawa Y, Tikoo A, Huynh J, Utermark T, Hanemann CO, Giovannini M, et al. A clue to the therapy of neurofibromatosis type 2: NF2/merlin is a PAK1 inhibitor. Cancer Journal. 2015;10(1):2010.1097/00130404-200401000-00006Suche in Google Scholar PubMed

Received: 2019-11-11
Accepted: 2019-01-20
Published Online: 2020-04-17

© 2020 Zhibao Wang et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

Artikel in diesem Heft

  1. Research Article
  2. MicroRNA-451b participates in coronary heart disease by targeting VEGFA
  3. Case Report
  4. A combination therapy for Kawasaki disease with severe complications: a case report
  5. Vitamin E for prevention of biofilm-caused Healthcare-associated infections
  6. Research Article
  7. Differential diagnosis: retroperitoneal fibrosis and oncological diseases
  8. Optimization of the Convolutional Neural Networks for Automatic Detection of Skin Cancer
  9. NEAT1 promotes LPS-induced inflammatory injury in macrophages by regulating miR-17-5p/TLR4
  10. Plasma matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 as prognostic biomarkers in critically ill patients
  11. Effects of extracorporeal magnetic stimulation in fecal incontinence
  12. Case Report
  13. Mixed germ cell tumor of the endometrium: a case report and literature review
  14. Bowel perforation after ventriculoperitoneal-shunt placement: case report and review of the literature
  15. Research Article
  16. Prognostic value of lncRNA HOTAIR in colorectal cancer : a meta-analysis
  17. Case Report
  18. Treatment of insulinomas by laparoscopic radiofrequency ablation: case reports and literature review
  19. Research Article
  20. The characteristics and nomogram for primary lung papillary adenocarcinoma
  21. Undiagnosed pheochromocytoma presenting as a pancreatic tumor: A case report
  22. Bioinformatics Analysis of the Expression of ATP binding cassette subfamily C member 3 (ABCC3) in Human Glioma
  23. Diagnostic value of recombinant heparin-binding hemagglutinin adhesin protein in spinal tuberculosis
  24. Primary cutaneous DLBCL non-GCB type: challenges of a rare case
  25. LINC00152 knock-down suppresses esophageal cancer by EGFR signaling pathway
  26. Case Report
  27. Life-threatening anaemia in patient with hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber syndrome)
  28. Research Article
  29. QTc interval predicts disturbed circadian blood pressure variation
  30. Shoulder ultrasound in the diagnosis of the suprascapular neuropathy in athletes
  31. The number of negative lymph nodes is positively associated with survival in esophageal squamous cell carcinoma patients in China
  32. Differentiation of pontine infarction by size
  33. RAF1 expression is correlated with HAF, a parameter of liver computed tomographic perfusion, and may predict the early therapeutic response to sorafenib in advanced hepatocellular carcinoma patients
  34. LncRNA ZEB1-AS1 regulates colorectal cancer cells by miR-205/YAP1 axis
  35. Tissue coagulation in laser hemorrhoidoplasty – an experimental study
  36. Classification of pathological types of lung cancer from CT images by deep residual neural networks with transfer learning strategy
  37. Enhanced Recovery after Surgery for Lung Cancer Patients
  38. Case Report
  39. Streptococcus pneumoniae-associated thrombotic microangiopathy in an immunosuppressed adult
  40. Research Article
  41. The characterization of Enterococcus genus: resistance mechanisms and inflammatory bowel disease
  42. Case Report
  43. Inflammatory fibroid polyp: an unusual cause of abdominal pain in the upper gastrointestinal tract A case report
  44. Research Article
  45. microRNA-204-5p participates in atherosclerosis via targeting MMP-9
  46. LncRNA LINC00152 promotes laryngeal cancer progression by sponging miR-613
  47. Can keratin scaffolds be used for creating three-dimensional cell cultures?
  48. miRNA-186 improves sepsis induced renal injury via PTEN/PI3K/AKT/P53 pathway
  49. Case Report
  50. Delayed bowel perforation after routine distal loopogram prior to ileostomy closure
  51. Research Article
  52. Diagnostic accuracy of MALDI-TOF mass spectrometry for the direct identification of clinical pathogens from urine
  53. The R219K polymorphism of the ATP binding cassette subfamily A member 1 gene and susceptibility to ischemic stroke in Chinese population
  54. miR-92 regulates the proliferation, migration, invasion and apoptosis of glioma cells by targeting neogenin
  55. Clinicopathological features of programmed cell death-ligand 1 expression in patients with oral squamous cell carcinoma
  56. NF2 inhibits proliferation and cancer stemness in breast cancer
  57. Body composition indices and cardiovascular risk in type 2 diabetes. CV biomarkers are not related to body composition
  58. S100A6 promotes proliferation and migration of HepG2 cells via increased ubiquitin-dependent degradation of p53
  59. Review Article
  60. Focus on localized laryngeal amyloidosis: management of five cases
  61. Research Article
  62. NEAT1 aggravates sepsis-induced acute kidney injury by sponging miR-22-3p
  63. Pericentric inversion in chromosome 1 and male infertility
  64. Increased atherogenic index in the general hearing loss population
  65. Prognostic role of SIRT6 in gastrointestinal cancers: a meta-analysis
  66. The complexity of molecular processes in osteoarthritis of the knee joint
  67. Interleukin-6 gene −572 G > C polymorphism and myocardial infarction risk
  68. Case Report
  69. Severe anaphylactic reaction to cisatracurium during anesthesia with cross-reactivity to atracurium
  70. Research Article
  71. Rehabilitation training improves nerve injuries by affecting Notch1 and SYN
  72. Case Report
  73. Myocardial amyloidosis following multiple myeloma in a 38-year-old female patient: A case report
  74. Research Article
  75. Identification of the hub genes RUNX2 and FN1 in gastric cancer
  76. miR-101-3p sensitizes non-small cell lung cancer cells to irradiation
  77. Distinct functions and prognostic values of RORs in gastric cancer
  78. Clinical impact of post-mortem genetic testing in cardiac death and cardiomyopathy
  79. Efficacy of pembrolizumab for advanced/metastatic melanoma: a meta-analysis
  80. Review Article
  81. The role of osteoprotegerin in the development, progression and management of abdominal aortic aneurysms
  82. Research Article
  83. Identification of key microRNAs of plasma extracellular vesicles and their diagnostic and prognostic significance in melanoma
  84. miR-30a-3p participates in the development of asthma by targeting CCR3
  85. microRNA-491-5p protects against atherosclerosis by targeting matrix metallopeptidase-9
  86. Bladder-embedded ectopic intrauterine device with calculus
  87. Case Report
  88. Mycobacterial identification on homogenised biopsy facilitates the early diagnosis and treatment of laryngeal tuberculosis
  89. Research Article
  90. The will of young minors in the terminal stage of sickness: A case report
  91. Extended perfusion protocol for MS lesion quantification
  92. Identification of four genes associated with cutaneous metastatic melanoma
  93. Case Report
  94. Thalidomide-induced serious RR interval prolongation (longest interval >5.0 s) in multiple myeloma patient with rectal cancer: A case report
  95. Research Article
  96. Voluntary exercise and cardiac remodeling in a myocardial infarction model
  97. Electromyography as an intraoperative test to assess the quality of nerve anastomosis – experimental study on rats
  98. Case Report
  99. CT findings of severe novel coronavirus disease (COVID-19): A case report of Heilongjiang Province, China
  100. Commentary
  101. Directed differentiation into insulin-producing cells using microRNA manipulation
  102. Research Article
  103. Culture-negative infective endocarditis (CNIE): impact on postoperative mortality
  104. Extracorporeal shock wave therapy for the treatment of chronic pelvic pain syndrome
  105. Plasma microRNAs in human left ventricular reverse remodelling
  106. Bevacizumab for non-small cell lung cancer patients with brain metastasis: A meta-analysis
  107. Risk factors for cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage
  108. Problems and solutions of personal protective equipment doffing in COVID-19
  109. Evaluation of COVID-19 based on ACE2 expression in normal and cancer patients
  110. Review Article
  111. Gastroenterological complications in kidney transplant patients
  112. Research Article
  113. CXCL13 concentration in latent syphilis patients with treatment failure
  114. A novel age-biomarker-clinical history prognostic index for heart failure with reduced left ventricular ejection fraction
  115. Case Report
  116. Clinicopathological analysis of composite lymphoma: A two-case report and literature review
  117. Trastuzumab-induced thrombocytopenia after eight cycles of trastuzumab treatment
  118. Research Article
  119. Inhibition of vitamin D analog eldecalcitol on hepatoma in vitro and in vivo
  120. CCTs as new biomarkers for the prognosis of head and neck squamous cancer
  121. Effect of glucagon-like peptide-1 receptor agonists on adipokine level of nonalcoholic fatty liver disease in rats fed high-fat diet
  122. 72 hour Holter monitoring, 7 day Holter monitoring, and 30 day intermittent patient-activated heart rhythm recording in detecting arrhythmias in cryptogenic stroke patients free from arrhythmia in a screening 24 h Holter
  123. FOXK2 downregulation suppresses EMT in hepatocellular carcinoma
  124. Case Report
  125. Total parenteral nutrition-induced Wernicke’s encephalopathy after oncologic gastrointestinal surgery
  126. Research Article
  127. Clinical prediction for outcomes of patients with acute-on-chronic liver failure associated with HBV infection: A new model establishment
  128. Case Report
  129. Combination of chest CT and clinical features for diagnosis of 2019 novel coronavirus pneumonia
  130. Research Article
  131. Clinical significance and potential mechanisms of miR-223-3p and miR-204-5p in squamous cell carcinoma of head and neck: a study based on TCGA and GEO
  132. Review Article
  133. Hemoperitoneum caused by spontaneous rupture of hepatocellular carcinoma in noncirrhotic liver. A case report and systematic review
  134. Research Article
  135. Voltage-dependent anion channels mediated apoptosis in refractory epilepsy
  136. Prognostic factors in stage I gastric cancer: A retrospective analysis
  137. Circulating irisin is linked to bone mineral density in geriatric Chinese men
  138. Case Report
  139. A family study of congenital dysfibrinogenemia caused by a novel mutation in the FGA gene: A case report
  140. Research Article
  141. CBCT for estimation of the cemento-enamel junction and crestal bone of anterior teeth
  142. Case Report
  143. Successful de-escalation antibiotic therapy using cephamycins for sepsis caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae bacteremia: A sequential 25-case series
  144. Research Article
  145. Influence factors of extra-articular manifestations in rheumatoid arthritis
  146. Assessment of knowledge of use of electronic cigarette and its harmful effects among young adults
  147. Predictive factors of progression to severe COVID-19
  148. Procedural sedation and analgesia for percutaneous trans-hepatic biliary drainage: Randomized clinical trial for comparison of two different concepts
  149. Acute chemoradiotherapy toxicity in cervical cancer patients
  150. IGF-1 regulates the growth of fibroblasts and extracellular matrix deposition in pelvic organ prolapse
  151. NANOG regulates the proliferation of PCSCs via the TGF-β1/SMAD pathway
  152. An immune-relevant signature of nine genes as a prognostic biomarker in patients with gastric carcinoma
  153. Computer-aided diagnosis of skin cancer based on soft computing techniques
  154. MiR-1225-5p acts as tumor suppressor in glioblastoma via targeting FNDC3B
  155. miR-300/FA2H affects gastric cancer cell proliferation and apoptosis
  156. Hybrid treatment of fibroadipose vascular anomaly: A case report
  157. Surgical treatment for common hepatic aneurysm. Original one-step technique
  158. Neuropsychiatric symptoms, quality of life and caregivers’ burden in dementia
  159. Predictor of postoperative dyspnea for Pierre Robin Sequence infants
  160. Long non-coding RNA FOXD2-AS1 promotes cell proliferation, metastasis and EMT in glioma by sponging miR-506-5p
  161. Analysis of expression and prognosis of KLK7 in ovarian cancer
  162. Circular RNA circ_SETD2 represses breast cancer progression via modulating the miR-155-5p/SCUBE2 axis
  163. Glial cell induced neural differentiation of bone marrow stromal cells
  164. Case Report
  165. Moraxella lacunata infection accompanied by acute glomerulonephritis
  166. Research Article
  167. Diagnosis of complication in lung transplantation by TBLB + ROSE + mNGS
  168. Case Report
  169. Endometrial cancer in a renal transplant recipient: A case report
  170. Research Article
  171. Downregulation of lncRNA FGF12-AS2 suppresses the tumorigenesis of NSCLC via sponging miR-188-3p
  172. Case Report
  173. Splenic abscess caused by Streptococcus anginosus bacteremia secondary to urinary tract infection: a case report and literature review
  174. Research Article
  175. Advances in the role of miRNAs in the occurrence and development of osteosarcoma
  176. Rheumatoid arthritis increases the risk of pleural empyema
  177. Effect of miRNA-200b on the proliferation and apoptosis of cervical cancer cells by targeting RhoA
  178. LncRNA NEAT1 promotes gastric cancer progression via miR-1294/AKT1 axis
  179. Key pathways in prostate cancer with SPOP mutation identified by bioinformatic analysis
  180. Comparison of low-molecular-weight heparins in thromboprophylaxis of major orthopaedic surgery – randomized, prospective pilot study
  181. Case Report
  182. A case of SLE with COVID-19 and multiple infections
  183. Research Article
  184. Circular RNA hsa_circ_0007121 regulates proliferation, migration, invasion, and epithelial–mesenchymal transition of trophoblast cells by miR-182-5p/PGF axis in preeclampsia
  185. SRPX2 boosts pancreatic cancer chemoresistance by activating PI3K/AKT axis
  186. Case Report
  187. A case report of cervical pregnancy after in vitro fertilization complicated by tuberculosis and a literature review
  188. Review Article
  189. Serrated lesions of the colon and rectum: Emergent epidemiological data and molecular pathways
  190. Research Article
  191. Biological properties and therapeutic effects of plant-derived nanovesicles
  192. Case Report
  193. Clinical characterization of chromosome 5q21.1–21.3 microduplication: A case report
  194. Research Article
  195. Serum calcium levels correlates with coronary artery disease outcomes
  196. Rapunzel syndrome with cholangitis and pancreatitis – A rare case report
  197. Review Article
  198. A review of current progress in triple-negative breast cancer therapy
  199. Case Report
  200. Peritoneal-cutaneous fistula successfully treated at home: A case report and literature review
  201. Research Article
  202. Trim24 prompts tumor progression via inducing EMT in renal cell carcinoma
  203. Degradation of connexin 50 protein causes waterclefts in human lens
  204. GABRD promotes progression and predicts poor prognosis in colorectal cancer
  205. The lncRNA UBE2R2-AS1 suppresses cervical cancer cell growth in vitro
  206. LncRNA FOXD3-AS1/miR-135a-5p function in nasopharyngeal carcinoma cells
  207. MicroRNA-182-5p relieves murine allergic rhinitis via TLR4/NF-κB pathway
https://doi.org/10.1515/med-2020-0042
Schlagwörter für diesen Artikel
NF2; breast cancer; stemness; proliferation
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Research Article
  2. MicroRNA-451b participates in coronary heart disease by targeting VEGFA
  3. Case Report
  4. A combination therapy for Kawasaki disease with severe complications: a case report
  5. Vitamin E for prevention of biofilm-caused Healthcare-associated infections
  6. Research Article
  7. Differential diagnosis: retroperitoneal fibrosis and oncological diseases
  8. Optimization of the Convolutional Neural Networks for Automatic Detection of Skin Cancer
  9. NEAT1 promotes LPS-induced inflammatory injury in macrophages by regulating miR-17-5p/TLR4
  10. Plasma matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 as prognostic biomarkers in critically ill patients
  11. Effects of extracorporeal magnetic stimulation in fecal incontinence
  12. Case Report
  13. Mixed germ cell tumor of the endometrium: a case report and literature review
  14. Bowel perforation after ventriculoperitoneal-shunt placement: case report and review of the literature
  15. Research Article
  16. Prognostic value of lncRNA HOTAIR in colorectal cancer : a meta-analysis
  17. Case Report
  18. Treatment of insulinomas by laparoscopic radiofrequency ablation: case reports and literature review
  19. Research Article
  20. The characteristics and nomogram for primary lung papillary adenocarcinoma
  21. Undiagnosed pheochromocytoma presenting as a pancreatic tumor: A case report
  22. Bioinformatics Analysis of the Expression of ATP binding cassette subfamily C member 3 (ABCC3) in Human Glioma
  23. Diagnostic value of recombinant heparin-binding hemagglutinin adhesin protein in spinal tuberculosis
  24. Primary cutaneous DLBCL non-GCB type: challenges of a rare case
  25. LINC00152 knock-down suppresses esophageal cancer by EGFR signaling pathway
  26. Case Report
  27. Life-threatening anaemia in patient with hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber syndrome)
  28. Research Article
  29. QTc interval predicts disturbed circadian blood pressure variation
  30. Shoulder ultrasound in the diagnosis of the suprascapular neuropathy in athletes
  31. The number of negative lymph nodes is positively associated with survival in esophageal squamous cell carcinoma patients in China
  32. Differentiation of pontine infarction by size
  33. RAF1 expression is correlated with HAF, a parameter of liver computed tomographic perfusion, and may predict the early therapeutic response to sorafenib in advanced hepatocellular carcinoma patients
  34. LncRNA ZEB1-AS1 regulates colorectal cancer cells by miR-205/YAP1 axis
  35. Tissue coagulation in laser hemorrhoidoplasty – an experimental study
  36. Classification of pathological types of lung cancer from CT images by deep residual neural networks with transfer learning strategy
  37. Enhanced Recovery after Surgery for Lung Cancer Patients
  38. Case Report
  39. Streptococcus pneumoniae-associated thrombotic microangiopathy in an immunosuppressed adult
  40. Research Article
  41. The characterization of Enterococcus genus: resistance mechanisms and inflammatory bowel disease
  42. Case Report
  43. Inflammatory fibroid polyp: an unusual cause of abdominal pain in the upper gastrointestinal tract A case report
  44. Research Article
  45. microRNA-204-5p participates in atherosclerosis via targeting MMP-9
  46. LncRNA LINC00152 promotes laryngeal cancer progression by sponging miR-613
  47. Can keratin scaffolds be used for creating three-dimensional cell cultures?
  48. miRNA-186 improves sepsis induced renal injury via PTEN/PI3K/AKT/P53 pathway
  49. Case Report
  50. Delayed bowel perforation after routine distal loopogram prior to ileostomy closure
  51. Research Article
  52. Diagnostic accuracy of MALDI-TOF mass spectrometry for the direct identification of clinical pathogens from urine
  53. The R219K polymorphism of the ATP binding cassette subfamily A member 1 gene and susceptibility to ischemic stroke in Chinese population
  54. miR-92 regulates the proliferation, migration, invasion and apoptosis of glioma cells by targeting neogenin
  55. Clinicopathological features of programmed cell death-ligand 1 expression in patients with oral squamous cell carcinoma
  56. NF2 inhibits proliferation and cancer stemness in breast cancer
  57. Body composition indices and cardiovascular risk in type 2 diabetes. CV biomarkers are not related to body composition
  58. S100A6 promotes proliferation and migration of HepG2 cells via increased ubiquitin-dependent degradation of p53
  59. Review Article
  60. Focus on localized laryngeal amyloidosis: management of five cases
  61. Research Article
  62. NEAT1 aggravates sepsis-induced acute kidney injury by sponging miR-22-3p
  63. Pericentric inversion in chromosome 1 and male infertility
  64. Increased atherogenic index in the general hearing loss population
  65. Prognostic role of SIRT6 in gastrointestinal cancers: a meta-analysis
  66. The complexity of molecular processes in osteoarthritis of the knee joint
  67. Interleukin-6 gene −572 G > C polymorphism and myocardial infarction risk
  68. Case Report
  69. Severe anaphylactic reaction to cisatracurium during anesthesia with cross-reactivity to atracurium
  70. Research Article
  71. Rehabilitation training improves nerve injuries by affecting Notch1 and SYN
  72. Case Report
  73. Myocardial amyloidosis following multiple myeloma in a 38-year-old female patient: A case report
  74. Research Article
  75. Identification of the hub genes RUNX2 and FN1 in gastric cancer
  76. miR-101-3p sensitizes non-small cell lung cancer cells to irradiation
  77. Distinct functions and prognostic values of RORs in gastric cancer
  78. Clinical impact of post-mortem genetic testing in cardiac death and cardiomyopathy
  79. Efficacy of pembrolizumab for advanced/metastatic melanoma: a meta-analysis
  80. Review Article
  81. The role of osteoprotegerin in the development, progression and management of abdominal aortic aneurysms
  82. Research Article
  83. Identification of key microRNAs of plasma extracellular vesicles and their diagnostic and prognostic significance in melanoma
  84. miR-30a-3p participates in the development of asthma by targeting CCR3
  85. microRNA-491-5p protects against atherosclerosis by targeting matrix metallopeptidase-9
  86. Bladder-embedded ectopic intrauterine device with calculus
  87. Case Report
  88. Mycobacterial identification on homogenised biopsy facilitates the early diagnosis and treatment of laryngeal tuberculosis
  89. Research Article
  90. The will of young minors in the terminal stage of sickness: A case report
  91. Extended perfusion protocol for MS lesion quantification
  92. Identification of four genes associated with cutaneous metastatic melanoma
  93. Case Report
  94. Thalidomide-induced serious RR interval prolongation (longest interval >5.0 s) in multiple myeloma patient with rectal cancer: A case report
  95. Research Article
  96. Voluntary exercise and cardiac remodeling in a myocardial infarction model
  97. Electromyography as an intraoperative test to assess the quality of nerve anastomosis – experimental study on rats
  98. Case Report
  99. CT findings of severe novel coronavirus disease (COVID-19): A case report of Heilongjiang Province, China
  100. Commentary
  101. Directed differentiation into insulin-producing cells using microRNA manipulation
  102. Research Article
  103. Culture-negative infective endocarditis (CNIE): impact on postoperative mortality
  104. Extracorporeal shock wave therapy for the treatment of chronic pelvic pain syndrome
  105. Plasma microRNAs in human left ventricular reverse remodelling
  106. Bevacizumab for non-small cell lung cancer patients with brain metastasis: A meta-analysis
  107. Risk factors for cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage
  108. Problems and solutions of personal protective equipment doffing in COVID-19
  109. Evaluation of COVID-19 based on ACE2 expression in normal and cancer patients
  110. Review Article
  111. Gastroenterological complications in kidney transplant patients
  112. Research Article
  113. CXCL13 concentration in latent syphilis patients with treatment failure
  114. A novel age-biomarker-clinical history prognostic index for heart failure with reduced left ventricular ejection fraction
  115. Case Report
  116. Clinicopathological analysis of composite lymphoma: A two-case report and literature review
  117. Trastuzumab-induced thrombocytopenia after eight cycles of trastuzumab treatment
  118. Research Article
  119. Inhibition of vitamin D analog eldecalcitol on hepatoma in vitro and in vivo
  120. CCTs as new biomarkers for the prognosis of head and neck squamous cancer
  121. Effect of glucagon-like peptide-1 receptor agonists on adipokine level of nonalcoholic fatty liver disease in rats fed high-fat diet
  122. 72 hour Holter monitoring, 7 day Holter monitoring, and 30 day intermittent patient-activated heart rhythm recording in detecting arrhythmias in cryptogenic stroke patients free from arrhythmia in a screening 24 h Holter
  123. FOXK2 downregulation suppresses EMT in hepatocellular carcinoma
  124. Case Report
  125. Total parenteral nutrition-induced Wernicke’s encephalopathy after oncologic gastrointestinal surgery
  126. Research Article
  127. Clinical prediction for outcomes of patients with acute-on-chronic liver failure associated with HBV infection: A new model establishment
  128. Case Report
  129. Combination of chest CT and clinical features for diagnosis of 2019 novel coronavirus pneumonia
  130. Research Article
  131. Clinical significance and potential mechanisms of miR-223-3p and miR-204-5p in squamous cell carcinoma of head and neck: a study based on TCGA and GEO
  132. Review Article
  133. Hemoperitoneum caused by spontaneous rupture of hepatocellular carcinoma in noncirrhotic liver. A case report and systematic review
  134. Research Article
  135. Voltage-dependent anion channels mediated apoptosis in refractory epilepsy
  136. Prognostic factors in stage I gastric cancer: A retrospective analysis
  137. Circulating irisin is linked to bone mineral density in geriatric Chinese men
  138. Case Report
  139. A family study of congenital dysfibrinogenemia caused by a novel mutation in the FGA gene: A case report
  140. Research Article
  141. CBCT for estimation of the cemento-enamel junction and crestal bone of anterior teeth
  142. Case Report
  143. Successful de-escalation antibiotic therapy using cephamycins for sepsis caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae bacteremia: A sequential 25-case series
  144. Research Article
  145. Influence factors of extra-articular manifestations in rheumatoid arthritis
  146. Assessment of knowledge of use of electronic cigarette and its harmful effects among young adults
  147. Predictive factors of progression to severe COVID-19
  148. Procedural sedation and analgesia for percutaneous trans-hepatic biliary drainage: Randomized clinical trial for comparison of two different concepts
  149. Acute chemoradiotherapy toxicity in cervical cancer patients
  150. IGF-1 regulates the growth of fibroblasts and extracellular matrix deposition in pelvic organ prolapse
  151. NANOG regulates the proliferation of PCSCs via the TGF-β1/SMAD pathway
  152. An immune-relevant signature of nine genes as a prognostic biomarker in patients with gastric carcinoma
  153. Computer-aided diagnosis of skin cancer based on soft computing techniques
  154. MiR-1225-5p acts as tumor suppressor in glioblastoma via targeting FNDC3B
  155. miR-300/FA2H affects gastric cancer cell proliferation and apoptosis
  156. Hybrid treatment of fibroadipose vascular anomaly: A case report
  157. Surgical treatment for common hepatic aneurysm. Original one-step technique
  158. Neuropsychiatric symptoms, quality of life and caregivers’ burden in dementia
  159. Predictor of postoperative dyspnea for Pierre Robin Sequence infants
  160. Long non-coding RNA FOXD2-AS1 promotes cell proliferation, metastasis and EMT in glioma by sponging miR-506-5p
  161. Analysis of expression and prognosis of KLK7 in ovarian cancer
  162. Circular RNA circ_SETD2 represses breast cancer progression via modulating the miR-155-5p/SCUBE2 axis
  163. Glial cell induced neural differentiation of bone marrow stromal cells
  164. Case Report
  165. Moraxella lacunata infection accompanied by acute glomerulonephritis
  166. Research Article
  167. Diagnosis of complication in lung transplantation by TBLB + ROSE + mNGS
  168. Case Report
  169. Endometrial cancer in a renal transplant recipient: A case report
  170. Research Article
  171. Downregulation of lncRNA FGF12-AS2 suppresses the tumorigenesis of NSCLC via sponging miR-188-3p
  172. Case Report
  173. Splenic abscess caused by Streptococcus anginosus bacteremia secondary to urinary tract infection: a case report and literature review
  174. Research Article
  175. Advances in the role of miRNAs in the occurrence and development of osteosarcoma
  176. Rheumatoid arthritis increases the risk of pleural empyema
  177. Effect of miRNA-200b on the proliferation and apoptosis of cervical cancer cells by targeting RhoA
  178. LncRNA NEAT1 promotes gastric cancer progression via miR-1294/AKT1 axis
  179. Key pathways in prostate cancer with SPOP mutation identified by bioinformatic analysis
  180. Comparison of low-molecular-weight heparins in thromboprophylaxis of major orthopaedic surgery – randomized, prospective pilot study
  181. Case Report
  182. A case of SLE with COVID-19 and multiple infections
  183. Research Article
  184. Circular RNA hsa_circ_0007121 regulates proliferation, migration, invasion, and epithelial–mesenchymal transition of trophoblast cells by miR-182-5p/PGF axis in preeclampsia
  185. SRPX2 boosts pancreatic cancer chemoresistance by activating PI3K/AKT axis
  186. Case Report
  187. A case report of cervical pregnancy after in vitro fertilization complicated by tuberculosis and a literature review
  188. Review Article
  189. Serrated lesions of the colon and rectum: Emergent epidemiological data and molecular pathways
  190. Research Article
  191. Biological properties and therapeutic effects of plant-derived nanovesicles
  192. Case Report
  193. Clinical characterization of chromosome 5q21.1–21.3 microduplication: A case report
  194. Research Article
  195. Serum calcium levels correlates with coronary artery disease outcomes
  196. Rapunzel syndrome with cholangitis and pancreatitis – A rare case report
  197. Review Article
  198. A review of current progress in triple-negative breast cancer therapy
  199. Case Report
  200. Peritoneal-cutaneous fistula successfully treated at home: A case report and literature review
  201. Research Article
  202. Trim24 prompts tumor progression via inducing EMT in renal cell carcinoma
  203. Degradation of connexin 50 protein causes waterclefts in human lens
  204. GABRD promotes progression and predicts poor prognosis in colorectal cancer
  205. The lncRNA UBE2R2-AS1 suppresses cervical cancer cell growth in vitro
  206. LncRNA FOXD3-AS1/miR-135a-5p function in nasopharyngeal carcinoma cells
  207. MicroRNA-182-5p relieves murine allergic rhinitis via TLR4/NF-κB pathway
Jetzt anmelden und 20% sparen
Institutioneller Zugang
Wie funktioniert Authentifizierung?
Haben Sie eine Idee, wie wir unsere Website verbessern können?
Bitte schreiben Sie uns.
© 2025 De Gruyter Brill
Heruntergeladen am 4.11.2025 von https://www.degruyterbrill.com/document/doi/10.1515/med-2020-0042/html
Button zum nach oben scrollen