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Osteoarthritis is a degenerative, painful and irreversible disease that affects millions of people worldwide. The causes and mechanisms of osteoarthritis have not been fully understood. Vitamin D is an essential factor in bone metabolism. Its actions are mediated by the vitamin D receptor, a transcription factor that controls gene expression, thus maintaining calcium and phosphate homeostasis. Vitamin D has been hypothesized to play essential role in a number of musculoskeletal diseases including osteoarthritis, and its deficiency is prevalent among osteoarthritis patients. A large number of studies have been done regarding the effects of vitamin D in pathogenesis and progression of osteoarthritis, as well as its use a therapeutic agent. Up to date, studies have provided controversial results, and no consensus concerning this matter was achieved. With this review, we aim to explore current data on the possible role of vitamin D and its receptor in pathogenesis of osteoarthritis and assess the efficiency of vitamin D supplementation as a therapeutic strategy.

Introduction. SARS-CoV2 2019 infection represent global problem. At this moment there is no vaccine or efficient treatment of infected patients. Treatment with blood plasma rich with anti SARS-CoV2 specific antibodies represents rare safe and effective treatment of Covid19 patients. Patients and Material. A total number of 950 patients were analyzed in this study, whose samples were collected in time interval from 01.05. till 15.08.2020. Patients were enrolled in study from Covid-19 hospitals, out-clinics and as family members of SARS-CoV2 infected patients. Original ELISA tests were developed to measure the concentration of anti-S1S2 Spike and anti-Nucleoprotein (IgG, IgA, IgM) SARS-CoV2 antibodies. Blood convalescent plasma was selectively collected from recovered patients according to specific antibodies concentration. Results. The highest concentrations of anti-S1S2 Spike or anti-Nucleoprotein specific IgG antibodies were detected in patients with the moderate/heavy clinical form of infection as well as in group of family members of SARS-CoV2 infected patients. Extremely high concentration of anti S1S2 Spike IgG and anti-Nucleoprotein IgG was demonstrated in 3% and 6% (respectively) of patients recovered from severe Covid19. From our hospitalized patients 63% and 51% had modest antibody levels (anti S1S2 Spike and anti-Nucleoprotein, respectively). After 60 days, in our selected donors’ concentration of anti S1S2 Spike IgG antibodies increased in 67%, paralleled with increase of anti-Nucleoprotein IgG antibodies in 58% of donors. Conclusion. Originally developed ELISA tests enable novel protocol for selection of convalescent blood plasma donor.

Background/Aim. Oral squamous cell carcinoma (OSCC) is the most common tumor type of head and neck carcinomas, characterized by a high recurrence rate and patients? poor survival. Further elucidation of the function and regulation of the TP53, a pivotal tumor suppressor gene, would provide advances in predicting the clinical behavior, prognosis, and chemotherapy response of OSCC patients. Thus, we investigated the association of TP53 gene mutations with survival and response to cisplatin chemotherapy in human papilloma virus (HPV)-negative OSCC patients. Methods. The potential clinical relevance of TP53 mutations was analyzed in 82 patients with HPV-negative OSCC. All patients underwent radiotherapy, and 25 patients received cisplatin chemotherapy. A negative HPV status was deter-mined by type-specific polymerase chain reaction (PCR) for high-risk HPV 16, 18, 31, and 33. Targeted sequencing of TP53 exons 4?8 was assessed by Sanger sequencing. Results. Of 82 HPV-negative OSCC patients, 49 (59.79%) had TP53 mutations, and 26 patients (31.7%) carried pathogenic TP53 mutations. Patients with pathogenic TP53 mutations had significantly reduced overall survival (p = 0.009). Recurrence status, but not TP53 mutations, was an independent marker of poor survival in our cohort [hazard ratio (HR) = 4.733, 95% confidence interval (95% CI): 2.027?11.053, p = 0.0001]. In the sub-cohort of patients who underwent cisplatin-based chemotherapy, pathogenic TP53 mutations were predictors of poor response to chemotherapy (p = 0.026). Conclusion. Our findings indicate that pathogenic TP53 mutations in HPV-negative OSCC tumors could be a prognostic marker of patients? reduced overall survival. In addition, pathogenic TP53 mutations in HPV-negative OSCC could be a marker of poor chemotherapy response of OSCC patients.

In adult organisms, deregulation of the sonic hedgehog (SHH) signaling pathway is significantly correlated with different malignancies. Currently, data associating genetic polymorphisms in the SHH pathway with melanoma are scarce and largely unknown. The objective of our study was to elucidate an association between gene polymorphisms in the SHH pathway and prognosis of melanoma skin cancer patients. The current study investigated the association of PTCH1 (rs357564), SMO (rs2228617) and GLI1 (rs2228224, rs2228226), polymorphisms with melanoma predisposition and prognosis. Single-nucleotide polymorphisms were assessed by TaqMan SNP Genotyping Assays. The study involved 93 melanoma patients and 97 individuals in the control group. Melanoma patients with the variant mutant genotype GG of GLI1 rs2228226 polymorphism had poorer overall survival and recurrence-free survival (P = 0.0001 and P = 0.037, respectively). The multivariate analysis revealed that disease progression [hazard ratio (HR) = 14.434, P = 0.0001] and the GLI1 rs2228226 polymorphism (HR = 4.161, P = 0.006) persisted as independent prognostic factors. Mutated allele carriers (combined heterozygous and mutated genotypes) for GLI1 rs2228224 G and GLI1 rs2228226 G allele significantly increased melanoma risk [odds ratio (OR) = 2.261, P = 0.007; OR = 2.176, P = 0.010]. Our study demonstrated that genetic variants in GLI1, downstream member of the HH signaling pathway, are the risk factors for melanoma susceptibility and it can be a novel marker for melanoma prognosis. As a crucial SHH signaling member, GLI1 can also be regarded as a novel drug target for anti-cancer treatment in melanoma.

Vitamin D receptor (VDR) gene polymorphisms could play a significant role in the susceptibility and pathogenesis of osteoarthritis (OA), the most common degenerative joint disorder in humans. The current study involved 94 OA patients and 100 healthy, asymptomatic controls. VDR variants FokI (rs2228570), TaqI (rs731236), ApaI (rs7975232) and EcoRV (rs4516035) were genotyped using TaqMan-based real-time PCR. Adjusted odds ratio (OR) analysis showed that VDR TaqI and FokI polymorphisms are significantly associated with susceptibility to OA (OR=1.986, P=0.001 and OR=1.561, P=0.017, respectively). Joint-specific analysis showed that the VDR TaqI polymorphism was associated with risk of hip OA (OR=1.930, P=0.005) and knee OA (OR=1.916, P=0.028), while the VDR FokI polymorphism was associated with higher risk of knee OA (OR=2.117, P=0.012). VDR TaqI and FokI polymorphisms are associated with the occurrence of persistent pain (P=0.005 and P=0.027, respectively), while ApaI was associated with a family history of OA (p=0.004). The VDR FokI and TaqI genetic variants significantly contribute to osteoarthritis susceptibility, the occurrence of persistent pain, and potentially to joint-specific OA risk.

Background/Aim. The inflammatory response is of utmost importance in bone healing, but the precise role of cells and cytokines remains unclear. In our study, we examined the association between interleukin-1? (IL-1?), tumor necrosis factors alpha (TNF-?), monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) concentrations, fracture configuration, and callus formation. Methods. Serum cytokine concentrations were determined in 78 non-obese children with long bone fractures (group 1), 10 children with finger fractures (group 2), and 10 healthy controls (group 3). Blood samples were taken immediately after fracture upon hospital admission for groups 1 and 2. Differences in cytokine concentrations were analyzed among groups and catego-rized according to fracture configuration and callus formation. Results. IL-1? and TNF-? levels were lower in patients that went on to produce incomplete callus compared with patients that formed complete callus. Surprisingly, the average IL-1? concentration was highest in the healthy control group. The only significant correlation between IL-1? and TNF-? was in the group with moderate callus formation. MCP-1 level was slightly increased in all patient groups compared to controls, with no mutual difference. An average IL-8 level showed a clear decrease tendency from the group with incompletely formed callus toward the group with completely formed callus compared to controls, without significant difference. Children with epiphysiolysis had the lowest concentrations of cytokines compared with all other fracture types including transverse, oblique, and spiral. There were significantly lower concentrations of IL-1? and MCP-1 in patients with less fragment displacement compared with patients with greater fragment displacement. Conclusion. The systemic inflammatory response is important in physiological bone healing. High early production of IL-1?, TNF-?, and MCP-1 is associated with greater callus formation and better healing outcome, while increased IL-8 level is associated with poor callus formation and worse healing outcome. Our results indicate that epiphysiolysis and larger fragment displacement are associated with delayed fracture healing.

Background/Aim. Lung cancer (LC) is one of the leading causes of mortality. Disease progression and advanced disease are characterized by the unprotective immune response due to M2 macrophage polarization, myeloid-derived suppressor cells (MDSC) activity, cytokine imbalance, and regulatory T lymphocyte activity. The aim of this study was to investigate the association between Th1/Th2 cytokines and CD14+B7H4+ monocyte (Mo) number in LC patients. Methods. We investigated principal Th1/Th2 cytokines and CD14+B7H4+ Mo number in blood and tumor microcirculation samples of 41 LC patients (III and IV clinical stage) and 30 healthy participants (control group). Results. The serum concentrations of investigated cytokines in all patients vs. heathy controls did not differ significantly. Stratification in groups according to tumor histology, disease extent, and tumor size revealed significant differences. LC patients with different histology types demonstrated significant differences, both in serum and tumor microcirculation samples. The presence of metastasis was associated with increased IFN-?/IL-4 in blood and increased IL-13 in tumor microcirculation samples. Tumor microcirculation samples of the largest tumors were characterized by the Th2 cytokine profile. Investigation of CD14+B7H4+ Mo in blood samples demonstrated a significant association of extreme value of this cell population with elevated IL-2/IL-13. Patients with the highest CD14+B7H4+ Mo number in tumor microcirculation samples demonstrated significant increments of IL-4, IL-13, IL-10, and TGF-?1. Conclusion. LC patients demonstrated polarization of cytokine response associated with microenvironment origin, tumor histology type, tumor size, and disease extent. The highest number of CD14+ B7H4+ monocytes is significantly associated with the Th2 cytokine profile.

Background/Aim. Recent data imply the significance of certain cytokines in the appearance and development of prostate cancer (PC), as well as their association with pathohistological and/or clinical characteristics of PC. The aim of this study was to examine the relationship between the IL-10 concentration with histopathological and clinical characteristics of PC patients. Methods. IL-10 concentration was determined in serum, urine and prostate massage secret (pms) samples of 88 CP patients (initially and after therapy), 20 benign prostatic hyperplasia (BPH) patients and 15 healthy controls. Results. Compared to BPH and control groups, PC patients had the highest average serum IL-10 concentration. Interestingly, BPH patients demonstrated the highest concentration of IL-6 in urine and pms samples. Also, patients with G3 gradus and with the highest Gleason score (4 + 4) demonstrated the highest IL-10 serum level. PC patients without any histopathological sign of tumor invasion had a significantly increased serum IL-10, either before or after the therapy, compared to the patient group with evident invasion of tumor cells. The therapy induced different IL-10 profile in serum and urine samples. After the therapy, there was a clear significant IL-10 increase in serum of patients with unfavorable Gleason score (4 + 4), with present infiltration of tumor cells in peritumoral tissue (lymphatic, vascular and combined) and in patients with high tumor volume. Conclusion. PC patients without any histopathological signs of tumor invasion before the therapy have significantly increased serum IL-10 concentration compared to those with the signs of tumor invasion. There is a clear dissociation of IL-10 values between a serum sample and local, urine and pms samples from a particular patient. After the therapy, high IL-10 serum concentration is present only in patients with high Gleason score, pre-sent infiltration of peritumoral tissue and high tumor volume.

Triple-negative breast cancer (TNBC) is characterized by aggressive phenotype and a poorer prognosis compared to the estrogen and progesterone receptor positive, Her2 negative (ER + PR + Her2-) breast cancer. Increasing evidence suggests that sirtuins, a family of histone deacetylases, could have an important role in aggressiveness of TNBC's. The current study evaluated the potential clinical relevance of SIRT1, SIRT3 and SIRT6 gene expressions in two prognostically distinctive subtypes of breast cancer, the most aggressive TNBC and the least aggressive ER + PR + Her2- tumors. Total RNAs were isolated from 48 TNBC and 63 ER + PR + Her2- tumor samples. Relative gene expression was determined by SYBR Green RT-PCR and delta-delta Ct method, normalized to GAPDH. Mean gene expression of both SIRT1 and SIRT3 was significantly lower in the TNBC compared to ER + PR + Her2- tumors (p = 0.0001). Low SIRT1 and SIRT6 expressions associated with worse overall survival in ER + PR + Her2- patients (p = 0.039, p = 0.006, respectively), while TNBC patients with high SIRT1 tend to have a poor prognosis (p = 0.057). In contrast, high expression of SIRT3 in TNBC patients associated with higher histological grade (p = 0.027) and worse overall survival (p = 0.039). The Cox regression analysis revealed that low SIRT1 expression could be an independent prognostic marker of poor survival in ER + PR + Her2- breast cancers (HR = 11.765, 95% CI:1.234-100, p = 0.033). Observed differential expression of SIRT1, SIRT3 and SIRT6 genes in TNBC and ER + PR + Her2- subtypes, with opposite effects on patients' survival, suggests context-dependent mechanisms underlying aggressiveness of breast cancer. Further investigations are necessary to evaluate sirtuins as potential biomarkers and therapeutic targets in breast cancer.

The aberrant DNA methylation plays a critical role in a number of different malignancies, including melanoma. DNA methylation is catalyzed by DNA methyltransferases (DNMTs), involved in methylation maintenance (DNMT1) and de novo DNA methylation (DNMT3A and DNMT3B). The current study investigated the association of genetic variants in the DNMT1 and DNMT3B with the clinicopathologic features and the clinical course of melanoma patients. In the present study, DNMT1 (rs2228612, rs2228611, and rs2114724) and DNMT3B (rs406193 and rs2424932) polymorphisms were examined in 123 melanoma patients. Single nucleotide polymorphisms were assessed using TaqMan SNPs Genotyping Assays according to the manufacturer's protocols. The carriers of the variant genotype of DNMT1 rs2228612 had poorer overall survival and recurrence-free survival, (P = 0.000 and 0.000, respectively), and an increased risk for adverse outcome [hazard ratio (HR) = 6.620, 95% confidence interval (CI): 2.214-19.791, P = 0.001]. DNMT1 rs2228612 was also associated with ulceration (P = 0.045), nodal status (P = 0.030), progression (P = 0. 007), and stage of disease (P = 0.003). Univariate analysis indicated that tumor-infiltrating lymphocytes could be a marker of good prognosis in melanoma patients (HR = 0.323, 95% CI: 0.127-0.855, P = 0.025), whereas the genotype distribution of the DNMT3B rs406193 polymorphism correlated significantly with the presence of tumor-infiltrating lymphocytes (P = 0.012). The multivariate analysis showed that the DNMT1 rs2228612 polymorphism (HR = 12.126, 95% CI: 2.345-62.715, P = 0.003) is an independent predictor of poor overall survival in melanoma patients. As expected, disease progression was also found to be an independent prognostic factor in melanoma patients (HR = 37.888, 95% CI: 3.615-397.062, P = 0.002). DNMT1 rs2228612 was found to be an independent predictor of poor overall survival in melanoma patients. DNMTs polymorphisms could serve as a potential target for novel therapeutic approaches.

Background/Aim. Recent studies indicate that adipokines have an important role in bone physiology and pathology. Recent data indicate that adipokine leptin functions as a regulator of bone growth at multiple levels, systemically and locally. So far, it has been shown that leptin influences bone volume and bone mineral density in a population with metabolic and/or hormonal abnormality. Data concerning leptin values in non-obese children with fractures are scarce. Methods. This study included 93 non-obese children with long bone fractures (LBF), 14 children with short bone fractures (SBF), and 19 healthy children. Leptin concentration was determined in two blood samples (day 0 and day 21) and analyzed according to gender, fracture type, anatomical localization of the fracture, fracture topography, callus formation, and the healing outcome. Results. Children with LBF demonstrated significantly increased leptin levels compared to the control group (both day 0/day 21). In the control group, girls had significantly more leptin than boys. Leptin value was significantly influenced by anatomical localization since boys and girls with humerus fracture and girls with femur fracture had the highest average leptin concentration in the initial sample. Boys with incomplete callus formation had the highest leptin concentration (both day 0/day 21), significantly elevated compared to boys' samples in the control group, boys' samples with an intermediary and well-formed callus, and also increased compared to the initial samples of girls with incomplete callus. Better callus formation in girls was associated with an increment of leptin concentrations in the second over the initial sample. Girls with partially and satisfactorily formed callus had significantly increased leptin concentration in the second sample (day 21) compared to the boys' group. Conclusion. Leptin concentration was significantly increased (both samples) in children with LBF compared to children with SBF and corresponding controls. Leptin concentration was highly influenced by gender. High blood leptin concentrations in boys or low leptin concentrations in girls immediately upon fracture could be used to identify groups of children with incomplete callus formation. Uvod/Cilj.Novijestudije pokazuju da adipokini imaju važnu ulogu u fiziologiji i patologiji kostiju. Takođe, najnoviji podaci pokazuju da adipokin leptin funkcioniše kao regulator rasta kostiju sistemski i lokalno. Pokazano je da leptin utiče na volumen kostiju i mineralnu gustinu kostiju u populaciji sa metaboličkom i/ili hormonskom abnormalnošću. Podaci o vrednostima leptina kod negojazne dece sa frakturama su oskudni. Metode. U ovu studijubil a su uključena93 negojazna deteta sa prelomima dugih kostiju (LBF), 14 dece sa prelomima malih kostiju (SBF) i 19 zdrave dece. Koncentracija leptina određena je u 2 uzorka krvi (0. danai 21 . dana) i analizirana prema polu, tipu frakture, lokalizaciji anatomske frakture, topografiji frakture, formiranju kalusa i ishodu zarastanja.Rezultati.Deca sa LBF imala su značajnopovećane nivoeleptina u poređenju sa kontrolnom grupom u oba uzorka krvi ( 0. dana/21 . dana). U kontrolnoj grupi devojčice su imale značajno više nivoe leptina od dečaka. Na vrednost leptina značajno je uticala anatomska lokalizacija, jer su dečaci i devojčice sa prelomom humerusa i devojčice sa prelomom femura imali najveću prosečnu koncentraciju leptina u početnom uzorku. Dečaci sa nepotpuno for miranim kalusom imali su najveću koncentraciju leptina (u oba uzorka, 0. dana/21. dana),značajno višuu odnosu na kontrolne uzorke dečaka, uzorke dečaka s intermedijarnim i dobro formiranim kalusom, a takođe višu u odnosu na koncentracije leptina u početnim uzorcima djevojčica s nepotpunim kalusom. Bolje formiranje kalusa kod devojčica je bilo povezano sa poveć anjem koncentracije leptina u drugom (21. dan) u odnosu na početni uzorak(0. dan). Devojčice sa delimično i zadovoljavajuće formiranim kalusom imale su značajno višu koncentraciju leptina u drugom uzorku (21. dan ) u odnosu na grupu dečaka. Zaključak. Koncentracija leptina je značajno povećana (u oba uzorkakrvi ) kod dece sa LBF u poređenju sa decom sa SBF i odgovarajućim kontrolama. Koncentracija leptina je zavisna od pola. Visok nivo leptina u krvi kod dečaka ili niska koncentracija leptina kod devojčica odmah nakon preloma može se koristiti za identifikaciju grupa dece sa nepotpunim formiranjem kalusa.

Background/Aim. Myeloid-derived suppressor cells (MDSCs) suppress immune responses via a series of inhibitory mechanisms, which ultimately could lead to tumor growth. B7-H4 expression is significantly associated with poor outcome and promotion of tumor cell proliferation, invasion and migration in patients with various cancers. Data concerning B7-H4 expression in lung cancers (LC), either on tumor or immunological cells, are still sporadic. The aim was to estimate and correlate the number of CD14+B7-H4+MDSCs in blood and lung tumor microcirculation with clinical stage, histology type of tumor, tumor node metastasis (TNM) stadium, nodal status and disease outspread. Methods. The study included 44 lung cancer patients (III and IV clinical stage) and 30 healthy controls. CD14+B7-H4+ MDSC number was estimated by flow cytometry in blood and tumor microcirculation samples of each patient. Results. CD14+B7-H4+ MDSCs number was significantly higher in patients? samples compared to controls. CD14+B7-H4+ MDSC number was significantly increased in tumor compared to blood sample of the same patient. Clinical stage III patients had the increased number of the CD14+B7-H4+ MDSC compared to stage IV, in both types of samples. According to histology, small cell lung cancer (SCLC) patients had the highest average CD14+B7-H4+ MDSCs number, significantly increased compared to patients with squamous and large cell LC histology type. Tumor size was directly associated with the number of the CD14+B7-H4+ MDSC, both in blood and tumor samples. Furthermore, nodal involvement was associated with the gradual increase of the CD14+B7-H4+ MDSC number, being the highest in the N3 group, again both in blood and tumor samples. Finally, we detected higher CD14+B7-H4+ MDSCs number in the samples of patients without metastases. Conclusion. CD14+B7-H4+ MDSCs n umber in L C patients is significantly associated with tumor histology type, lymph node involvement, disease extent degree and tumor size. Concerning their large number in LC tumor microenvironment together with immunosuppressive capacities, CD14+B7-H4+ MDSCs could represent important tumor promoting factor in LC pathophysiology.

Osteoarthritis (OA) is a progressive degenerative disease that affects all synovial joints, causing the disability of the main locomotor diarthrodial joints. OA pathogenesis is caused by a complex interplay between a number of genetic and environmental risk factors, involved in the early onset and progression of this chronic inflammatory joint disease. Uncovering the underlying immunological and genetic mechanisms will enable an insight into OA pathophysiology and lead to novel and integrative approaches in the treatment of OA patients, together with a reduction of the disease risk, or a delay of its onset in susceptible patients.

ObjectivesGenetic variants in the hedgehog signaling pathway and VDR gene are involved in inflammatory responses and neoplastic transformation. Current study investigated whether single-nucleotide polymorphisms in the hedgehog pathway genes PTCH1, GLI1, SMO, and VDR contribute to susceptibility to odontogenic cystic lesions, odontogenic keratocysts, or inflammatory radicular cysts.Material and methodsCurrent study examined polymorphisms of PTCH1 (rs357564) and PTCH1 insertion (IVS1-83), GLI1 (rs2228224, rs2228226), SMO (rs2228617), and VDR (rs2228570, rs731236, rs7975232). A case-control study was conducted on 41 keratocyst cases, 43 radicular cyst cases, and control group of 93 healthy individuals without cystic lesions, radiographically confirmed. Single-nucleotide polymorphisms were assessed by real-time and TaqMan SNP genotyping assays, while PTCH1 insertion 18bp IVS1-83 polymorphism was determined by PCR.ResultsThe difference in genotype distribution between keratocyst cases and control group was observed for PTCH1 IVS1-83 and GLI1 rs2228224 polymorphism (p=0.022, p=0.030, respectively). Homozygous mutant GG genotype within GLI1 rs2228224 is associated with increased susceptibility for odontogenous keratocysts, with adjusted odds ratio of 4.098 (confidence interval of 1.482-11.328, p=0.007).ConclusionGLI1 rs2228224 and PTCH1 polymorphisms could predispose to odontogenic keratocysts.Clinical relevanceVariants in hedgehog signaling pathway genes, such as GLI1 and PTCH1, and vitamin D receptor gene, might be considered as molecular risk factors in odontogenic cystic lesions and potential targets for novel therapeutic approaches.

Aim: It was the aim of the study to identify commonly deregulated miRNAs in oral cancer patients by performing a meta-analysis of previously published miRNA expression profiles in cancer and matched normal non-cancerous tissue in such patients. Material and methods: Meta-analysis included seven independent studies analyzed by a vote-counting method followed by bioinformatic enrichment analysis. Results: Amongst seven independent studies included in the meta-analysis, 20 miRNAs were found to be deregulated in oral cancer when compared with non-cancerous tissue. Eleven miRNAs were consistently up-regulated in three or more studies (miR-21-5p, miR-31-5p, miR-135b-5p, miR-31-3p, miR-93-5p, miR-34b-5p, miR-424-5p, miR-18a-5p, miR-455-3p, miR-450a-5p, miR-21-3p), and nine were down-regulated (miR-139-5p, miR-30a-3p, miR-376c-3p, miR-885-5p, miR-375, miR-486-5p, miR-411-5p, miR-133a-3p, miR-30a-5p). The meta-signature of identified miRNAs was functionally characterized by KEGG enrichment analysis. Twenty-four KEGG pathways were significantly enriched, and TGF-beta signaling was the most enriched signaling pathway. The highest number of meta-signature miRNAs was involved in the sphingolipid signaling pathway. Natural killer cell-mediated cytotoxicity was the pathway with most genes regulated by identified miRNAs. The rest of the enriched pathways in our miRNA list describe different malignancies and signaling. Conclusions: The identified miRNA meta-signature might be considered as a potential battery of biomarkers when distinguishing oral cancer tissue from normal, non-cancerous tissue. Further mechanistic studies are warranted in order to confirm and fully elucidate the role of deregulated miRNAs in oral cancer. Supplemental data at [https://doi.org/10.6084/m9.figshare.5926675]

Summary Association of vitamin D receptor (VDR) gene polymorphisms with sepsis risk and mortality was studied. VDR FokI CC genotype was associated with increased sepsis risk (OR = 13.396, p = .000009) compared to the TT genotype. Results suggest possible role of VDR FokI (rs2228570) as a molecular biomarker of increased sepsis risk.

Aims: To evaluate the association between catechol-O-methyltransferase (COMT) gene polymorphisms and temporomandibular disorders (TMD), TMD pain, psychosocial impairment related to TMD, and postoperative pain. Methods: A total of 90 patients with a diagnosis of painful TMD and 92 matched controls were investigated for the presence of TMD, TMD pain, and psychosocial variables by the Research Diagnostic Criteria for TMD. In a prospective cohort study of 40 subjects who underwent extraction of at least one fully impacted mandibular third molar, subjects had 6 months post-surgery follow-up of postoperative pain. DNA extracted from peripheral blood was genotyped for three COMT polymorphisms (rs4680, rs6269, and rs165774) by real-time TaqMan method. The association between COMT polymorphisms and clinical variables was determined by calculating odds ratios (OR) and their 95% confidence intervals (CI). Results: Homozygous AA genotype and heterozygous variant A allele carriers (genotype AG/AA) for rs165774 polymorphism were associated with increased risk of TMD compared to wild type (wt) GG genotype (OR = 9.448, P = .006; OR = 2.088, P = .017, respectively). In addition, AA genotype was associated with increased risk of arthralgia (OR = 4.448, P = .011), myofascial pain (OR = 3.543, P = .035), and chronic TMD pain (OR = 6.173, P = .006), compared to wt genotype. AA genotype for rs6269 polymorphism was related to less postoperative chronic TMD pain (P = .025) and lower postoperative acute pain at the extraction site (P = .030). No associations with depression and somatization were observed. Conclusion: AA genotype of rs165774 could be a significant risk factor for the development of TMD and TMD pain, while AA genotype of rs6269 presents less postoperative chronic TMD pain and acute pain at a dental extraction site.

Oral Diseases (2011) 17, 794–800 Objectives: Recent studies indicate various molecular abnormalities in oral squamous cell carcinomas (OSCC), including DNA methylation of tumor-associated genes. Although promoter hypermethylation of Wnt pathway antagonists RUNX3 (Runt-related transcription factor 3) and Wnt inhibitory factor 1 (WIF1) has been identified as a common event in a number of carcinomas, methylation status and the role of RUNX3 as a possible tumor suppressor in oral and head and neck cancer are yet controversial. The aim of our study is to determine the occurrence of RUNX3 and WIF1 genes hypermethylation and correlation with tumor and host-related factors and prognosis in tongue carcinomas. Material and Methods: In 76 patients with tongue carcinoma, RUNX3 and WIF1 genes promoter hypermethylation analysis was assessed by nested methylation-specific PCR method. Results: Hypermethylation of WIF1 and RUNX3 genes promoters was observed in 35% and 25% of carcinomas, respectively. RUNX3 gene promoter hypermethylation was significantly associated with lymph node involvement (P = 0.013) and tumor stage (P = 0.006), but not with the overall survival. Occurrence of RUNX3 and WIF1 genes comethylation was associated with nodal status (P = 0.058) and tumor stage (P = 0.055). Conclusions: Our findings indicate that RUNX3 and WIF1 are frequently aberrantly methylated and that RUNX3 promoter methylation could be considered as a potential prognostic marker in tongue carcinoma.

The purpose of this study was to evaluate the associations of variability in pulp sensitivity with sex, psychosocial variables, the gene that encodes for the enzyme catechol-O-methyltransferase (COMT), and chronic painful conditions (temporomandibular disorders [TMDs]).The study was composed of 97 subjects (68 women and 29 men aged 20-44 years). The electric (electric pulp tester) and cold (refrigerant spray) stimuli were performed on mandibular lateral incisors. The results were expressed as pain threshold values for electric pulp stimulation (0-80 units) and as pain intensity scores (visual numeric scale from 0-10) for cold stimulation. The Research Diagnostic Criteria for TMD were used to assess TMD, depression, and somatization. DNA extracted from peripheral blood was genotyped for 3 COMT polymorphisms (rs4680, rs6269, and rs165774) using the real-time TaqMan method. Multivariate linear regression was used to investigate the joint effect of the predictor variables (clinical and genetic) on pulp sensitivity (dependent variables).Threshold responses to electric stimuli were related to female sex (P .01) and the homozygous GG genotype for the rs165774 polymorphism (P .05). Pain intensity to cold stimuli was higher in TMD patients (P .01) and tended to be higher in women. Multivariate linear regression identified sex and the rs165774 COMT polymorphism as the determinants of electric pain sensitivity, whereas TMD accounts for the variability in the cold response.Our findings indicate that sex/a COMT gene variant and TMD as a chronic painful condition may contribute to individual variation in electric and cold pulp sensitivity, respectively.

The current study investigated the association between VDR EcoRV (rs4516035), FokI (rs2228570), ApaI (rs7975232) and TaqI (rs731236), CYP27B1 (rs4646536), CYP24A1 (rs2296241), and MTHFR (rs1801133) gene polymorphisms and risk of oral lichen planus (OLP) occurrence. The study group consisted of 65 oral lichen planus patients and 100 healthy blood donors in the control group. Single nucleotide polymorphisms were genotyped by real time PCR or PCR-restriction fragment length polymorphism (RFLP) method. Heterozygous as well as mutated genotype of vitamin D receptor (VDR) FokI (rs2228570) polymorphism was associated with increased oral lichen planus risk in comparison with wild type genotype (odds ratio (OR) = 3.877, p = 0.017, OR = 38.153, p = 0.001, respectively). A significantly decreased OLP risk was observed for heterozygous genotype of rs2296241 polymorphism in CYP24A1 gene compared with the wild type form (OR = 0.314, p = 0.012). VDR gene polymorphisms ApaI and TaqI were in linkage disequilibrium (D’ = 0.71, r 2 = 0.22). Identified haplotype AT was associated with decreased OLP risk (OR = 0.592, p = 0.047). Our results highlight the possible important role of VDR FokI (rs2228570) and CYP24A1 rs2296241 gene polymorphisms for oral lichen planus susceptibility. Identification of new molecular biomarkers could potentially contribute to determination of individuals with OLP predisposition.

Previous studies have reported that vitamin D receptor (VDR) gene polymorphisms are associated with the occurrence of various cancers, including melanoma. The aim of the current study was to investigate the association of VDR gene polymorphisms with melanoma risk, clinicopathological characteristics, and vitamin D levels. The study group included 117 patients (84 patients with superficial spreading melanoma and 33 patients with nodular melanoma). The control group included 122 sex-matched and age-matched healthy-blood donors of the same ethnicity. VDR gene polymorphisms FokI, EcoRV, TaqI, and ApaI were genotyped by real-time PCR. In 60 patients, the total 25-hydroxyvitamin D levels were evaluated in serum samples by direct chemiluminescence. Associations among parameters were considered to be significant if the P value was less than 0.05. Significant differences in the frequencies of VDR genotypes were observed between cases and the control group for FokI and TaqI polymorphisms (P

Objective. Several studies have suggested that the metabolism of alcohol is modulated by the polymorphisms in genes encoding ethanol-metabolizing enzymes, including alcohol dehydrogenase 1C, ADH1C, and cytochrome P450-dependent monooxygen- ase, CYP2E1. Genetic polymorphisms of ethanol-metabolizing enzymes may affect individual susceptibility to oral cancer. The purpose of this study was to investigate the associations between ADH1C and CYP2E1 gene polymorphisms with oral squamous cell carcinoma in an ethnically homogeneous Cau- casian population. Design. Case-control study. Setting. Serbian national general hospital. Subjects and Methods. The study was conducted on 123 oral cancer patients and a control group of 177 individuals of the Caucasian race and the same ethnicity, matched in age and gender, without previous cancer history. The control group consisted of 120 population-based and 57 hospital-based con- trols of heavy-drinking individuals. Genetic polymorphisms of ADH1C SspI, ADH1C HaeIII, CYP2E1 RsaI, and CYP2E1 Ins were determined by the polymerase chain reaction and restriction fragment length polymorphisms. Results. After adjustment by potential confounders, the significant increase of oral cancer risk, independent of alcohol drinking, was observed in individuals with the variant ADH1C SspI*2/*2 genotype (odds ratio, 3.029; P = .014) and in combined ADH1C SspI*1/*2 and ADH1C SspI*2/*2 genotypes (odds ratio, 2.605; P = .002), compared to the ADH1C*1/1* wild type. The associa- tion of other polymorphisms under study was not observed. Conclusion. This study suggested that the ADH1C SspI poly- morphism could play a significant role in the etiology of oral cancer, whereas ADH1C HaeIII, CYP2E1 RsaI, and CYP2E1 Ins could have minor influence.