Potential molecular mechanism in self-renewal is associated with miRNA dysregulation in sacral chordoma - A next-generation RNA sequencing study.

Background: Chordoma, the most frequent malignant primary spinal neoplasm, characterized by a high rate of recurrence, is an orphan disease where the clarification of the molecular oncogenesis would be crucial to developing new, effective therapies. Dysregulated expression of non-coding RNAs, especially microRNAs (miRNA) has a significant role in cancer development. Methods: Next-generation RNA sequencing (NGS) was used for the combinatorial analysis of mRNA-miRNA gene expression profiles in sacral chordoma and nucleus pulposus samples. Advanced bioinformatics workflow was applied to the data to predict miRNA-mRNA regulatory networks with altered activity in chordoma. Results: A large set of significantly dysregulated miRNAs in chordoma and their differentially expressed target genes have been identified. Several molecular pathways related to tumorigenesis and the modulation of the immune system are predicted to be dysregulated due to aberrant miRNA expression in chordoma. We identified a gene set including key regulators of the Hippo pathway, which is targeted by differently expressed miRNAs, and validated their altered expression by RT-qPCR. These newly identified miRNA/RNA interactions are predicted to have a role in the self-renewal process of chordoma stem cells, which might sustain the high rate of recurrence for this tumor. Conclusions: Our results can significantly contribute to the designation of possible targets for the development of anti-chordoma therapies.

Genetic variants of interleukin 1B and 6 are associated with clinical outcome of surgically treated lumbar degenerative disc disease.

BACKGROUND: Successfully surgically treating degenerative disc diseases can be challenging to the spine surgeons, the long-term outcome relies on both the physical and mental status of the patient before and after treatment. Numerous studies underlined the role of inflammatory cytokines - like interleukin 1B and 6 - in the development of chronic diseases such as failed back surgery syndrome (FBSS) and major depressive disorder (MDD) which alter the outcome after spinal surgery. Our aim was to evaluate the associations of IL6 and IL1B gene polymorphisms with the long-term outcome of degenerative lumbar spine surgeries. METHODS: An international genetical database (GENODISC) was combined with our institute's clinical database to create a large pool with long term follow up data. Altogether 431 patient's data were analysed. Patient reported outcome measures and surgical outcome was investigated in association with IL1B and IL6 SNPs with the help of 'SNPassoc' R genome wide association package. RESULTS: Interleukin 1B variants analysis confirmed association with improvement of pain after surgery on individual SNP level and on haplotype level, moreover relationship with patient reported outcome and preoperative level of depression was found on individual SNP level. IL6 variants were associated with preoperative depression, somatization and with subsequent surgery. CONCLUSION: Understanding the complexity of spinal surgery patients' long-term well-being is crucial in effectively treating chronic debilitating somatic diseases and the associated mental illnesses. Further studies should investigate more comprehensively the linkage of chronic physical and mental illnesses focusing on their simultaneous treatment.

Outcome of group physical therapy treatment for non-specific low back pain patients can be predicted with the cross-culturally adapted and validated Hungarian version STarT back screening tool.

PURPOSE: The STarT Back Tool was developed to identify the specific modifiable prognostic factors for non-specific low back pain and to classify the patients into risk groups; low, medium and high risk of chronicity. Applied therapeutic approaches often involve group physical therapy. The aim of this study was the cross-cultural adaptation and validation of the Hungarian version of the STarT Back Tool and to investigate the predictive ability for global treatment outcome. MATERIALS AND METHODS: A prospective cohort study (N = 133) was carried out involving non-specific low back pain patients. Internal consistency, construct validity, reliability and prognostic discriminative ability have been investigated. After 3 months of treatment global outcome was evaluated. RESULTS: A 2-factor structure was found, with moderate internal consistency (Cronbach α = 0.89 for the total and psychosocial subscale 0.62). Between the Hungarian STarT Back Tool, the Oswestry Disability Index, leg pain, low back pain, Tampa Scale for Kinesiophobia, Fear Avoidance Beliefs Questionnaire and the physical subscale of the quality of life questionnaire, significant good to excellent- correlation was found (r > 0.41). The test-retest analysis showed excellent reliability (Intraclass Correlation Coefficient = 0.93) with standard error measurement being 0.49 (minimal detectable change = 1.37). The Area Under the Curve for baseline STarT Back Tool scores was 0.7 and 0.8 for global treatment outcome and distress, respectively. The Area Under the Curve for global treatment outcome versus STarT risk groups proved to be 0.76 representing adequate discriminative ability. CONCLUSION: The successful cross-cultural adaptation was followed by the validity analysis and as a result the Hungarian version of the STarT Back Tool proved to be a reliable and valid tool in the identification of risk groups of chronicity for patients with low back pain. Patients allocated to the high-risk group were more likely experiencing poor outcome at 3 months follow up, thus it can be used to predict outcome if treated with group physical therapy.Implication for rehabilitationLow back pain is a multifactorial disease where physical and psychosocial risk factors play a role in the development and prognosis of the disease.The STarT-H can be considered as a reliable, valid measurement tool in the identification of risk groups of chronicity for patients with low back pain.Clinical relevance of the STarT-H is that it can be used to stratify patients into risk groups of chronicity in different Hungarian speaking healthcare settings.According to our findings the STarT-H can also be applied to predict global treatment outcome in low back pain patients if treated with group physical therapy.

Global Treatment Outcome after Surgical Site Infection in Elective Degenerative Lumbar Spinal Operations.

Background: Surgical site infection (SSI) is a serious complication after routine lumbar spinal operations, and its effect on global treatment outcome (GTO) is less reported. The aim of the current study was to measure the impact of SSI on outcome, which was evaluated with patient reported outcome measures (PROMs) and patients' subjective judgment (GTO). Methods: A total of 910 patients underwent primary a single- or two-level lumbar decompression or instrumented fusion surgical procedure. Patients completed Visual Analogue Scale (VAS), Oswestry Disability Index (ODI), and Core Outcome Measurement Index (COMI) at baseline and at two-year follow-up. The rate of improvement in PROMs was measured for the total cohort and the group of patients with SSI. Patients evaluated GTO on a five-point Likert scale. This study was approved by the Scientific and Research Ethics Committee of the Medical Research Council (number: 29970-3/2015/EKU) and the Institutional Review Board. Results: Regardless of the presence of SSI, significant improvement was measured in all PROMs without any difference in the rate of change between the clinical subgroups (non-SSI vs. SSI, dODI: p = 0.370, dCOMI: p = 0.383, dVAS: p = 0.793). In the total cohort, 87.3% of patients reported good outcome (N% = 87.3%). After an SSI, however, more patients (25.7%) reported poor outcome compared with those without the complication (chi-square test: value = 5.66; df = 1; p = 0.017; odds ratio = 2.49). Conclusions: Patients with successfully treated SSI can expect as good objective clinical result as patients without SSI while the subjective treatment outcome can be worse. The GTO could also be improved in complicated cases, however, with more extensive peri-operative patient education and information considering the patients' expectations, too.

Correction to: Association of vitamin D receptor gene polymorphisms with disc degeneration.

Unfortunately, the following reference was missed out in the original publication.

Association of vitamin D receptor gene polymorphisms with disc degeneration.

PURPOSE: Numerous candidate genes and single-nucleotide polymorphisms (SNPs) have been identified in the background of lumbar disc degeneration (LDD). However, in most of these underpowered studies, definitions of LDD are inconsistent; moreover, many of the findings have not been replicated and are contradictory. Our aim was to characterize LDD by well-defined phenotypes and possible endophenotypes and analyse the association between these and candidate vitamin D receptor (VDR) gene polymorphisms on a large (N = 1426) dataset. METHODS: Seven candidate VDR SNPs were genotyped. Individual association, haplotype and gene-gene interaction analyses were performed. All degenerative endophenotypes were significantly associated with one or more candidate VDR gene variants. RESULTS: Haplotype analyses confirmed the association between the 3'-end VDR variants (BsmI, ApaI, TaqI) and Modic changes as well as the relationship of 5'-end variants (Cdx2, A1012G) with endplate defects. We also found significant interactions between the 3'- and 5'-end regulatory regions and endplate defects. Based on our results, VDR and its gene variants are highly associated with specific degenerative LDD endophenotypes. CONCLUSION: Understanding relationships between phenotype and gene variants is crucial for describing the pathways leading to the multifactorial, polygenic degeneration process and LDD-related conditions. These slides can be retrieved under Electronic Supplementary Material.

GM-CSF and GM-CSF receptor have regulatory role in transforming rat mesenteric mesothelial cells into macrophage-like cells.

OBJECTIVE AND DESIGN: During peritonitis, mesothelial cells assume macrophage characteristics, expressing macrophage markers, indicating that they might differentiate into macrophage-like cells. MATERIALS AND SUBJECTS: Twenty-five male rats were used for in vivo experiments. For in vitro experiments, a primary mesentery culture model was developed. The mesothelial cell to macrophage-like cell transition was followed by studying ED1 expression. TREATMENTS: In vitro primary mesenteric culture was treated with granulocyte-macrophage colony-stimulating factor (GM-CSF, 1 ng/ml). Blocking internalization of receptor-ligand complex, Dynasore (80 µM) was used. Acute peritonitis was induced by Freund's adjuvant's (1 ml) intraperitoneal injection. RESULTS: Immunohistochemistry: GM-CSF in vitro treatment resulted in a prominent ED1 expression in transformed mesothelial cells. Blocking the internalization, ED1 expression could not be detected. GM-CSF receptor (both α and ß) was expressed in mesothelial cells in vitro (even if the GM-CSF was not present) and in vivo. Inflammation resulted in an increasing GM-CSF and GM-CSF-receptor level in the lysate of mesothelial cells. CONCLUSIONS: Mesothelial cells can differentiate into macrophage-like cells, and GM-CSF, produced by the mesothelial cells, has probably an autocrine regulatory role in this transition. Our results provide new data about the plasticity of mesothelial cell and support the idea that during inflammation macrophages can derive from non-hematopoietic sources as well.