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Odontogenic tumors are rare neoplasms arising from the odontogenic apparatus. We aimed to identify molecular characteristics associated with odontogenic tumorigenesis and malignancy. To this end, we investigated the expression level of human genes by using, for the first time in odontogenic tumors, the technique of expression profiling. Gene expression alterations common to all six odontogenic tumors were identified by the use of cDNA microarrays containing 19,000 human cDNAs. Statistical analysis on a subset of 4974 cDNAs present in the biopsies identified 506 distinct genes associated with the tumors (p-value < 0.01). Gene ontology analysis of the cellular processes which were differentially regulated in odontogenic tumors was accomplished by the use of a subset of 1409 annotated genes. Finally, 43 cDNAs differentiated the three malignant odontogenic tumors (ameloblastic carcinoma, clear cell odontogenic tumor, granular cell odontogenic tumor) from the three benign ameloblastoma biopsies (p < 0.01). The identified genes might help us better classify borderline odontogenic tumors. [ABSTRACT FROM AUTHOR]

Objective: The study objectives were (i) to explore the agreement between the Outcome Measures in Rheumatology (OMERACT) ultrasound lesions of enthesitis and physical examination in assessing enthesitis in patients with spondyloarthritis (SpA) and (ii) to investigate the prevalence and clinical relevance of subclinical enthesitis in this population., Methods: Twenty rheumatology centers participated in this cross-sectional study. Patients with SpA, including axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA), underwent both ultrasound scan and physical examination of large lower limb entheses. The OMERACT ultrasound lesions of enthesitis were considered, along with a recently proposed definition for "active enthesitis" by our group. Subclinical enthesitis was defined as the presence of "active enthesitis" in ≥1 enthesis in patients with SpA without clinical enthesitis (ie, number of positive entheses on physical examination and Leeds Enthesitis Index score = 0)., Results: A total of 4,130 entheses in 413 patients with SpA (224 with axSpA and 189 with PsA) were evaluated through ultrasound and physical examination. Agreement between ultrasound and physical examination ranged from moderate (ie, enthesophytes) to almost perfect (ie, power Doppler and "active enthesitis"). Patellar tendon entheses demonstrated the highest agreement, whereas Achilles tendon insertion showed the lowest. Among 158 (38.3%) of 413 patients with SpA with clinical enthesitis, 108 (68.4%) exhibited no "active enthesitis" on ultrasound. Conversely, of those 255 without clinical enthesitis, 39 (15.3%) showed subclinical enthesitis. Subclinical enthesitis was strongly associated with local structural damage. However, no differences were observed regarding the demographic and clinical profiles of patients with SpA with and without subclinical enthesitis., Conclusion: Our study underscores the need for a comprehensive tool integrating ultrasound and physical examination for assessing enthesitis in patients with SpA., (© 2024 American College of Rheumatology.)

The aim of this paper is to identify factors associated with interstitial lung disease (ILD) in patients with systemic sclerosis (SSc) and build an algorithm to better define this association for a personalised application in clinical practice., Methods: A total of 78 SSc patients underwent HRCT to assess ILD. Demographic, clinical and laboratory variables were collected, focusing on those associated either directly or indirectly with lung involvement. The discriminant value of each variable was determined using the operating characteristic curves (ROC) and included in a model to estimate the strength of ILD association in SSc., Results: Thirty-three (42.31%) patients showed ILD on HRCT. DLco, M-Borg, GERD-Q and capillary density were significantly associated with the presence of ILD-SSc. A model including these variables had a coefficient of determination (R 2 ) of 0.697. DLco had an AUC of 0.861 ( p < 0.001) with a cut-off of ≤72.3% (sensitivity 78.8%, specificity 91.1%, +LR 8.86). The m-Borg Scale showed an AUC of 0.883 ( p < 0.001) with a cut-off >2 (sensitivity 84.8%, specificity 82.2%, +LR 4.77), GERD-Q had an AUC of 0.815 ( p < 0.001) with a cut-off >7 (sensitivity 72.7%, specificity 86.7%, +LR 5.45). The capillary density showed an AUC of 0.815 ( p < 0.001) with a cut-off of ≤4.78 (sensitivity 87.9%, specificity 68.9%, +LR 2.82). Based on the pre-test probability values, these four variables were applied to Fagan's nomogram to calculate the post-test probability of this association., Conclusions: Our study identified four associated clinical factors of ILD in SSc patients. Moreover, their inclusion in an algorithm for the post-test probability, tailored to the specific patients' characteristics, significantly increases the ability to find out the presence of SSc-ILD.

Objectives: To assess, in spondyloarthritis (SpA), the discriminative value of the Outcome Measures in Rheumatology (OMERACT) ultrasound lesions of enthesitis and their associations with clinical features in this population., Methods: In this multicentre study involving 20 rheumatology centres, clinical and ultrasound examinations of the lower limb large entheses were performed in 413 patients with SpA (axial SpA and psoriatic arthritis) and 282 disease controls (osteoarthritis and fibromyalgia). 'Active enthesitis' was defined as (1) power Doppler (PD) at the enthesis grade ≥1 plus entheseal thickening and/or hypoechoic areas, or (2) PD grade >1 (independent of the presence of entheseal thickening and/or hypoechoic areas)., Results: In the univariate analysis, all OMERACT lesions except enthesophytes/calcifications showed a significant association with SpA. PD (OR=8.77, 95% CI 4.40 to 19.20, p<0.001) and bone erosions (OR=4.75, 95% CI 2.43 to 10.10, p<0.001) retained this association in the multivariate analysis. Among the lower limb entheses, only the Achilles tendon was significantly associated with SpA (OR=1.93, 95% CI 1.30 to 2.88, p<0.001) in the multivariate analyses. Active enthesitis showed a significant association with SpA (OR=9.20, 95% CI 4.21 to 23.20, p<0.001), and unlike the individual OMERACT ultrasound lesions it was consistently associated with most clinical measures of SpA disease activity and severity in the regression analyses., Conclusions: This large multicentre study assessed the value of different ultrasound findings of enthesitis in SpA, identifying the most discriminative ultrasound lesions and entheseal sites for SpA. Ultrasound could differentiate between SpA-related enthesitis and other forms of entheseal pathology (ie, mechanical enthesitis), thus improving the assessment of entheseal involvement in SpA., Competing Interests: Competing interests: ADM has received speaking fees from Janssen and has received support for attending meetings by Galapagos outside the submitted work. GS has received speaking fees and support for attending meetings by Novartis outside the submitted work. EC has received speaking fees from Novartis outside the submitted work. EDD has received speaking fees from Novartis and has received support for attending meetings by AbbVie outside the submitted work. MF has received speaking fees from Galapagos, AbbVie, Boehringer Ingelheim, Lilly and GSK and has received support for attending meetings by Pfizer outside the submitted work. XM has received speaking fees from AbbVie, Lilly Novartis, UCB and Janssen and has received support for attending meetings by UCB and Janssen outside the submitted work. MGR has received speaking fees from AbbVie, Raffo and Tecnofarma outside the submitted work. HM-O has received research grants from Janssen, Novartis, Pfizer and UCB and honoraria/speaker fees from AbbVie, Amgen, Eli Lilly, Janssen, Moonlake, Novartis, Pfizer, Takeda and UCB non-relevant to the submitted work. WG has received speaking fees from Accademia di Medicina, Janssen, Angelini Ethos, Galapagos, Biopharma and UVET outside the submitted work. EF has received speaking fees from AbbVie, Amgen, BMS, Janssen, Lilly, Novartis, Pfizer and Union Chimique Belge Pharma outside the submitted work., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objectives: We aimed to 1) evaluate by power Doppler (PD) ultrasound (US) the response to therapy of the most inflamed joint and enthesis (target sites) in psoriatic arthritis (PsA) patients starting a biologic disease-modifying anti-rheumatic drug (bDMARD); and 2) to investigate the correlation between the US response and clinical data., Methods: Consecutive PsA patients with US synovitis and US 'active' enthesitis, starting a bDMARD, were included. The joint with the highest OMERACT-EULAR-US composite score and the enthesis with the highest PD grade (targets) were identified at baseline. The US examination and clinical assessment were performed at 0, 3 and 6 months. The response of OMERACT-EULAR-US synovitis composite score was defined as reaching a grade = 0 at follow-up examination; synovial and entheseal PD responses were defined as a PD=0 and/or a reduction of ≥2 PD grades at follow-up examination., Results: Thirty patients were included. Synovitis composite score, synovial PD and entheseal PD showed significant responses at 3 and 6 months compared to baseline (p<0.01). Synovial PD responses were higher than entheseal PD responses at 3 months (71.4% vs 40.0%, p=0.01) and 6 months (77.8% vs. 46.7%, p=0.02). US synovitis responses were correlated with DAPSA (p<0.01) and MDA responses (p=0.01 for composite score, p=0.02 for PD)., Conclusions: US was found sensitive for monitoring treatment response in PsA patients starting a biologic drug. Entheseal PD was less responsive than synovial PD, suggesting that enthesitis may represent a 'difficult-to-treat' domain in PsA.

The objective of this study is to estimate the prevalence of US findings indicative of calcium pyrophosphate deposition (CPPD) in patients with knee pain. Consecutive patients with knee pain, equally distributed among males and females in seven different age-decades (21-90 years), were enrolled in a cross-sectional study. The presence of US OMERACT-defined CPPD (medial and lateral menisci and femoral hyaline cartilage) and osteophytes (medial and lateral compartments of the tibiofemoral joint) was scored as presence/absence in both knees. Four hundred twenty participants were enrolled (210 men/210 women). Fibrocartilage and hyaline cartilage CPPDs were detected by US in 94/420 (22.4%) and 41/420 (9.8%) participants, respectively. No significant sex differences were noted. The prevalence and the extent of CPPD increased with age. Fibrocartilage and hyaline cartilage CPPDs were identified in 0/60 participants in the third decade, and in 28/60 (46.7%) and 14/60 (23.3%) participants in the ninth decade, respectively (p for trend < 0.01). While fibrocartilage and hyaline cartilage CPPD is virtually absent in subjects younger than 40 and 50 years old, their prevalence steeply increases above from these age groups. Age (aIRR, 1.03; 95% CI, 1.02-1.05), osteophyte score (aIRR, 1.40; 95% CI, 1.22-1.60), and hyaline cartilage CPPD score (aIRR, 2.68; 95% CI, 2.06-3.49) were associated with fibrocartilage CPPD score, whereas age (aIRR, 1.02; 95% CI, 1.01-1.05) and fibrocartilage CPPD score (aIRR, 2.92; 95% CI, 2.29-3.72) were associated with hyaline cartilage CPPD score in multivariable negative binomial regression analyses. In conclusion, we report the US prevalence of CPPD in patients with knee pain. Fibrocartilage CPPD occurs at a younger age and is more prevalent than hyaline cartilage CPPD. Key points • Fibrocartilage CPPD occurs at a younger age and is more prevalent than hyaline cartilage CPPD. • Fibrocartilage and hyaline cartilage CPPDs are virtually absent in subjects younger than 40 and 50 years old. • In subjects older than 80 years, fibrocartilage and hyaline cartilage CPPD prevalence rises up to 46.7% and 23.3%, respectively., (© 2023. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Introduction: The impact of COVID-19 pandemic represents a serious challenge for 'frail' patients' populations with inflammatory autoimmune systemic diseases such as systemic sclerosis (SSc). We investigated the prevalence and severity of COVID-19, as well the effects of COVID-19 vaccination campaign in a large series of SSc patients followed for the entire period (first 38 months) of pandemic., Patients and Method: This prospective survey study included 1755 unselected SSc patients (186 M, 1,569F; mean age 58.7 ± 13.4SD years, mean disease duration 8.8 ± 7.3SD years) recruited in part by telephone survey at 37 referral centers from February 2020 to April 2023. The following parameters were carefully evaluated: i. demographic, clinical, serological, and therapeutical features; ii. prevalence and severity of COVID-19; and iii. safety, immunogenicity, and efficacy of COVID-19 vaccines., Results: The prevalence of COVID-19 recorded during the whole pandemic was significantly higher compared to Italian general population (47.3 % vs 43.3 %, p < 0.000), as well the COVID-19-related mortality (1.91 % vs 0.72 %, p < 0.001). As regards the putative prognostic factors of worse outcome, COVID-19 positive patients with SSc-related interstitial lung involvement showed significantly higher percentage of COVID-19-related hospitalization compared to those without (5.85 % vs 1.73 %; p < 0.0001), as well as of mortality rate (2.01 % vs 0.4 %; p = 0.002). Over half of patients (56.3 %) received the first two plus one booster dose of vaccine; while a fourth dose was administered to 35.6 %, and only few of them (1.99 %) had five or more doses of vaccine. Of note, an impaired seroconversion was recorded in 25.6 % of individuals after the first 2 doses of vaccine, and in 8.4 % of patients also after the booster dose. Furthermore, the absence of T-cell immunoreactivity was observed in 3/7 patients tested by QuantiFERON® SARSCoV-2 Starter Set (Qiagen). The efficacy of vaccines, evaluated by comparing the COVID-19-related death rate recorded during pre- and post-vaccination pandemic periods, revealed a quite stable outcome in SSc patients ( death rate from 2.54 % to 1.76 %; p = ns), despite the significant drop of mortality observed in the Italian general population (from 2.95 % to 0.29 %; p < 0.0001)., Conclusions: An increased COVID-19 prevalence and mortality rate was recorded in SSc patients; moreover, the efficacy of vaccines in term of improved outcomes was less evident in SSc compared to Italian general population. This discrepancy might be explained by concomitant adverse prognostic factors: increased rate of non-responders to vaccine in SSc series, low percentage of individuals with four or more doses of vaccine, ongoing immunomodulating treatments, disease-related interstitial lung disease, and/or reduced preventive measures in the second half of pandemic. A careful monitoring of response to COVID-19 vaccines together with adequate preventive/therapeutical strategies are highly recommendable in the near course of pandemic in this frail patients' population., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Alessandro Antonelli reports financial support was provided by Italian 10.13039/100009647Ministry of Health, Ricerca Finalizzata (RF-2021-12374986) Destinatario istituzionale: Regione Toscana. Unità Operative:U.O.1: Azienda Ospedaliero-Universitaria Pisana; U.O.2: Azienda Ospedaliero-Universitaria Aldo Moro Bari; U.O.3: Azienda Ospedaliero-Universitaria Modena, CUP Master: D55E22000670001., (© 2023 Published by Elsevier B.V.)

Background: Rapid urease test (RUT) is a diagnostic tool for Helicobacter pylori (H. pylori) diagnosis, based on the ability of the bacterium to produce urease. Despite it is considered simple, fast, and cheap, some conditions may cause false negativity. Therefore, the aim of this study was to compare RUT with currently recommended tests for H. pylori diagnosis., Methods: We enrolled consecutive patients who underwent upper endoscopy with histology, RUT, and urea breath test (UBT). Delta over baseline (DOB) >4% was considered positive for UBT. Diagnosis of infection was achieved when at least two tests were positive. The rate of false positivity of RUT was computed, and DOB value in RUT+ versus RUT- was compared by Mann-Whitney Test., Results: One hundred and sixteen consecutive patients with H. pylori infection were recruited. The male/female ratio was 35/81 and the mean age 45.2±13.1. Twenty-five patients (21.5%) were RUT-, despite being positive at both histology and UBT. On the other hand, in only two patients UBT and histology had discordant results. A full concordance of the three tests was observed in 89 patients (76.7%). DOB, additionally, was significantly higher in RUT+ patients (39.2±24.2%) than RUT- ones (26.3±18.5%; P=0.005)., Conclusions: RUT shows false negativity rate higher than 20%. Moreover, the RUT-negative patients showed a lower DOB at UBT, which is an indirect indicator of intragastric bacterial load. Therefore, it is presumable that H. pylori low amount may be a concurrent cause of false negativity. This study suggests that RUT-based H. pylori detection should be restricted to some specific conditions.

Objectives: To better define the spectrum of new-onset post-COVID-19 and post-COVID-19 vaccine inflammatory rheumatic diseases (IRD) from a large multicentric observational study., Methods: Consecutive cases of IRD encountered during a 12-month period and satisfying one of the following inclusion criteria: (a) onset of the rheumatic manifestations within 4 weeks from SARS-CoV-2 infection or (b) onset of the rheumatic manifestations within 4 weeks from the administration of one of the COVID-19 vaccines ws recruited., Results: The final analysis cohort comprised 267 patients, of which 122 (45.2%) in the post-COVID-19 and 145 (54.8%) in the postvaccine cohort. Distribution of IRD categories differed between the two cohorts: the post-COVID-19 cohort had a higher percentage of patients classified as having inflammatory joint diseases (IJD, 52.5% vs 37.2%, p=0.013) while the post-vaccine cohort had a higher prevalence of patients classified as polymyalgia rheumatica (PMR, 33.1% vs 21.3%, p=0.032). No differences were detected in the percentage of patients diagnosed with connective tissue diseases (CTD 19.7% vs 20.7%, p=0.837) or vasculitis (6.6% vs 9.0%, p=0.467). Despite the short follow-up period, IJD and PMR patients' response to first-line therapy was favourable, with both groups achieving a drop in baseline disease activity scores of ~30% and ~70% respectively., Conclusion: Our article reports the largest cohort published to date of new-onset IRD following SARS-CoV-2 infection or COVID-19 vaccines. Although causality cannot be ascertained, the spectrum of possible clinical manifestations is broad and includes IJD, PMR, CTD and vasculitis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To investigate the inter/intra-reliability of ultrasound (US) muscle echogenicity in patients with rheumatic diseases., Methods: Forty-two rheumatologists and 2 radiologists from 13 countries were asked to assess US muscle echogenicity of quadriceps muscle in 80 static images and 20 clips from 64 patients with different rheumatic diseases and 8 healthy subjects. Two visual scales were evaluated, a visual semi-quantitative scale (0-3) and a continuous quantitative measurement ("VAS echogenicity," 0-100). The same assessment was repeated to calculate intra-observer reliability. US muscle echogenicity was also calculated by an independent research assistant using a software for the analysis of scientific images (ImageJ). Inter and intra reliabilities were assessed by means of prevalence-adjusted bias-adjusted Kappa (PABAK), intraclass correlation coefficient (ICC) and correlations through Kendall's Tau and Pearson's Rho coefficients., Results: The semi-quantitative scale showed a moderate inter-reliability [PABAK = 0.58 (0.57-0.59)] and a substantial intra-reliability [PABAK = 0.71 (0.68-0.73)]. The lowest inter and intra-reliability results were obtained for the intermediate grades (i.e., grade 1 and 2) of the semi-quantitative scale. "VAS echogenicity" showed a high reliability both in the inter-observer [ICC = 0.80 (0.75-0.85)] and intra-observer [ICC = 0.88 (0.88-0.89)] evaluations. A substantial association was found between the participants assessment of the semi-quantitative scale and "VAS echogenicity" [ICC = 0.52 (0.50-0.54)]. The correlation between these two visual scales and ImageJ analysis was high (tau = 0.76 and rho = 0.89, respectively)., Conclusion: The results of this large, multicenter study highlighted the overall good inter and intra-reliability of the US assessment of muscle echogenicity in patients with different rheumatic diseases., Competing Interests: SA received honoraria from AbbVie, Celgene, UCB, Novartis, Janssen, Pfizer, and Sanofi. AB served as a speaker for AbbVie, Amgen, Sanofi-Genzyme, and UCB, outside the submitted work. EF had received speaking fees from AbbVie, Amgen, BMS, Janssen, Lilly, Novartis, Roche, Pfizer, and UCB, outside the submitted work. WG had received speaking fees from Celltrion and Pfizer, outside the submitted work., (Copyright © 2023 Di Matteo, Moscioni, Lommano, Cipolletta, Smerilli, Farah, Airoldi, Aydin, Becciolini, Bonfiglioli, Carotti, Carrara, Cazenave, Corradini, Cosatti, de Agustin, Destro Castaniti, Di Carlo, Di Donato, Di Geso, Elliott, Fodor, Francioso, Gabba, Hernández-Díaz, Horvath, Hurnakova, Jesus, Marin, Martire, Mashadi Mirza, Massarotti, Musca, Nair, Okano, Papalopoulos, Rosa, Rosemffet, Rovisco, Rozza, Salaffi, Scioscia, Scirè, Tamas, Tanimura, Ventura-Rios, Villota-Eraso, Villota, Voulgari, Vreju, Vukatana, Hereter, Zanetti, Grassi and Filippucci.)

Objective: To explore the association of the Outcome Measures in Rheumatology ultrasound (US) entheseal abnormalities with the presence of US joint bone erosions in psoriatic arthritis (PsA)., Methods: Consecutive patients with PsA were included in this cross-sectional study. Demographic and clinical variables were collected. A bilateral US assessment was carried out at the following entheses: plantar fascia, and the quadriceps, patellar (proximal and distal), and Achilles tendons. The following US entheseal abnormalities were registered: hypoechogenicity, thickening, Doppler signal < 2 mm from the bony cortex, calcification/enthesophyte, and bone erosion. The presence of US joint bone erosions was investigated at the second and fifth metacarpophalangeal joints, ulnar head, and fifth metatarsophalangeal (MTP) joint, bilaterally, as well as at the level of the most inflamed joint on physical examination. Multiple linear regression analysis was performed to identify clinical and/or US variables associated with US-detected joint bone erosions., Results: A total of 104 patients with PsA were enrolled. At least 1 joint bone erosion was found in 47 of 104 patients (45.2%). Bone erosions were most frequently detected at the fifth MTP joint level (42/208 joints [20.2 %] in 32/104 patients [30.8%]). In the multivariate model, only a power Doppler (PD) signal at the enthesis ( P < 0.001, standardized β = 0.51), bone erosions at the enthesis ( P = 0.02, standardized β = 0.20), PsA disease duration ( P = 0.04, standardized β = 0.17), and greyscale joint synovitis ( P = 0.03, standardized β = 0.42) were associated with US-detected joint bone erosions., Conclusion: PD signal and bone erosions at the enthesis represent sonographic biomarkers of a more severe subset of PsA in terms of US-detected joint erosive damage., (Copyright © 2023 by the Journal of Rheumatology.)

Despite SARS-CoV-2 transmission being a complex phenomenon, greater population density seems to be a risk factor. The aim of this study was to analyze through an epidemiologic urban health approach the relationship between population density and SARS-CoV-2 incidence using data which are comparable with regard to testing strategies. All 10,300 SARS-CoV-2 confirmed cases between October and December 2020 were included. We conducted separate analysis by gender standardizing and stratifying by age and month. In the Province Capital (p.d.=765 inhabitants/km2), standardized SARS-CoV-2 incidence rate was higher than the expected, both in men (SIR=1.17, 95%CI=1.12;1.22, p&lt;0.0001) and women (SIR=1.20, 95%CI=1.15;1.25, p&lt;0.0001). In municipalities with p.d. &gt;200 inhabitants/km2, standardized SARS-CoV-2 incidence rate was similar to the expected (p&gt;0.05). In municipalities with p.d. &lt;200 inhabitants/km2, standardized SARS-CoV-2 incidence rate was lower than the expected, both in men (SIR=0.85, 95%CI=0.81;0.90, p&lt;0.0001) and women (SIR=0.84, 95%CI=0.80;0.88, p&lt;0.0001). Stratified analysis by months with likelihood ratio test showed heterogeneity of the p.d. effect in men and women (p&lt;0.05). SARS-CoV-2 incidence rate seemed to be higher in most densely populated areas, both in men and women. Our results confirmed the great importance of restrictive measures as well as the importance of limiting the epidemic wave in the initial stages and could help guide pandemic management strategies according to urban context and population density.

Classification and prognosis of larynx squamous cell carcinoma (LSCC) depends on clinical and histopathological examination. Currently, expression profiling harbors the potential to investigate, classify, and better manage cancer. Gene expression profiles of 22 primary LSCCs were analyzed by microarrays containing 19,200 cDNAs. GOAL functionally classified differentially expressed genes, and a novel "in silico" procedure identified physical gene clusters differentially transcribed. A signature of 158 genes differentiated tumors with nodal metastasis. A novel statistical method allowed categorization of metastatic tumors into 2 distinct subgroups of differential gene expression patterns. Among genes correlated to nodal metastatic progression, we verified in vitro that NM23-H3 reduced cell motility and TRIM8 were a growth suppressor. Six chromosomal regions were specifically downregulated in metastatic tumors. This large-scale gene expression analysis in LSCC provides information on changes in genomic activity associated with lymphonodal metastasis and identifies molecules that might prove useful as novel therapeutic targets.

Objective: To retrospectively investigate whether the genetic profile from chorionic villous sampling (CVS) found in euploid fetuses with increased NT differs from matched controls., Study Design: We employed cDNA microarray technology to characterize and compare the gene expression profile of chorionic villous tissues (which encompass the trophoblast and inner mesenchymal core) belonging to four singleton male fetuses with increased NT at 10-11 weeks' gestation. A pool of four normal chorionic villous tissues belonging to four respective fetuses, matched for gestational age and gender, was used as controls., Results: In euploid fetuses, we found several underexpressed genes, possibly involved in mechanisms associated with the abnormal NT thickness. All these genes are likely to belong to the mesenchymal core of the villus that originates from the extraembryonic mesoderm, and thus might be closely representative of the embryonic genetic profile. They include: (1) genes of embryonic development and differentiation such as Endothelin 3 (EDN3) and secreted frizzled-related protein 4 (SFRP4); (2) genes of the extracellular matrix (ECM) metabolism such as tissue inhibitor of metalloproteinase1 (TIMP1), and disintegrin-like and matrix metalloproteinase (MMP) (reprolysin type) with thrombospondin type 1 Motif or ADAMTS2, exostoses (multiple)-like 1 (EXTL1), heparan sulfate (HS) 6-O-sulfotransferase 1 or HS6ST1, fibronectin 1 (FN1) and Integrin Alpha 10 (ITGA10) involved in HS and proteoglycan bio-synthesis, ECM synthesis and cell-matrix adhesion; (3) genes involved in vessel formation and differentiation such as angiogenic factor (VG5Q), and in blood pressure control and muscle contraction, like Endothelin 3 or EDN3 and sarcolemma associated protein (SLMAP). Such lower expressions of the villous tissues might be related to an immature genetic profile of the embryo development as well as abnormal regulation of ECM bio-synthesis and/or improper vessel growth and blood pressure control. Also, the results partially support the theories proposed for NT enlargement such as altered composition of ECM and abnormal/delayed development of the circulatory system., Conclusions: Abnormal extraembryonic genetic expression is found at 10-11 weeks' gestation in euploid fetuses with increased NT. If both extra- and intraembryonic mesoderms express the same genetic alterations, then microarray analyses on CVS could be used to screen several mesoderm-derivate anomalies., (Copyright 2006 John Wiley & Sons, Ltd.)

Cisplatin [cis-diamminedichloroplatinum(II)] (CDDP) is an organic compound that is widely used for the treatment of a large number of tumors. Its clinical use is limited by the presence of some undesired side effects, like as oto- and nephro toxicity, whose mechanisms of action are not understood. One of the possible CDDP toxicity mechanism seems to involve the generation of reactive oxygen species (ROS), that can impair morphology and function of hair cells (HC) in the organ of Corti. To test this hypothesis we evaluated the effect of CDDP treatment on RNA steady-state levels of 15,000 genes by microarray analysis, using, as a experimental model, the OC-k3 cell line, obtained from the organ of Corti of transgenic mice and constitutively expressing the large SV40 T antigen. We have found overexpression of several genes related to arachidonate mobilization including phospholipase A2, group IV and V, phospholipase A2 activating protein and lysophospholipase I and III, as well as lipoxygenation like arachidonate 12-lipoxygenase and arachidonate 5-lipoxygenase activating protein. In addition, we found significant transcription of genes regulating cell respiration, including cyt c oxidase, as well as genes involved in xenobiotic detoxification and lipid peroxidation such as cyt P450, and other oxidases including spermine oxidase and monoamine oxidase. As a whole, overexpression of the group of different genes seems to indicate that an oxidative burst could take place during cisplatin administration. We therefore searched for evidences of superoxide anion and hydrogen peroxide by means of electron paramagnetic resonance (EPR) spectroscopy and flow cytometry, but failed to detect them. On the other hand, we found an increase of malondialdehyde (MDA) synthesis and protein carbonylation products, indicating the occurence of lipid peroxidative degradation. When we tested the effectiveness of butylated hydroxytoluene (BHT), dithiothreitol (DTT) and N-acetylcysteine (N-Ac) as cytoprotectants, all of them reduced protein carbonylation to control levels and significantly protected OC-k3 from CDDP-induced cell death, with an higher protection when using the lipophylic antioxidant BHT. The same antioxidants prevented also the onset of protein carbonylation, which extent was decreased to basal levels. These data indicate that CDDP is able to stimulate gene expression up to 12 h after the beginning of the treatment. This increase in gene transcription involves a large number of genes potentially able to increase the level of cell ROS. Consistently, cells survival is improved by cotreatment with antioxidants, in particular lipophilics.

One of the most common problems encountered while deciphering results from expression profiling experiments is in relating differential expression of genes to molecular functions and cellular processes. A second important problem is that of comparing experiments performed by different labs using different microarray platforms, or even unrelated techniques. Gene Ontology (GO) is now used to describe biological features, since GO terms are associated with genes, to overcome the apparent distance between expression profiles and biological comprehension. Here we describe the development, implementation and use of GOAL (Gene Ontology Automated Lexicon), a web-based application for the identification of functions and processes regulated in microarray and SAGE (serial analysis of gene expression) experiments. We applied GOAL to a range of experimental datasets related to different biological problems, including cancer and the cell cycle. By using GOAL, reported and novel relevant processes were identified in a number of experiments by our collaborators and by us. Different datasets could also be compared with each other to define conserved functional modules. GOAL allows a seamless and high-level analysis of expression profiles and is implemented as a free WWW resource (http://microarrays.unife.it).

Surface implant modifications have been shown to have a relevant importance in modifying cell response. Expression profiling by DNA microarray is a new molecular technology that allows the analysis of gene expression in a cell system. By using DNA microarrays containing 19,200 genes, we identified in osteoblast-like cells line (MG-63) on new implant surface (nanoPORE, Out-Link, Sweden and Martina, Due Carrare, Padova, Italy), several genes whose expressions were significantly down-regulated. The differentially expressed genes cover a broad range of functional activities: (a) immunity, (b) vesicular transport (c) apoptosis and cell cycle regulation. It was also possible to detect some genes whose function is unknown. The data reported are, to our knowledge, the first genetic portrait of an implant surface. They can be relevant to better understand the molecular mechanism of implant osseointegration and as a model for comparing other materials.

Zirconium oxide ceramics have outstanding mechanical properties, a high biocompatibility and a high resistance to scratching. Expression profiling by DNA microarray is a molecular technology that allows the analysis of gene expression in a cell system. By using DNA microarrays containing 19,200 genes, we identified in osteoblast-like cells line (MG-63) cultured on zirconium oxide discs (Cercon, Degussa Dental, Hanau, Germany) several genes whose expression was significantly up or down-regulated. The differentially expressed genes cover a broad range of functional activities: (a) immunity, (b) vesicular transport and (c) cell cycle regulation. It was also possible to detect some genes whose function is unknown. The data reported are, to our knowledge, the first genetic portrait of a zirconium oxide surface. They can be relevant to better understand the molecular mechanism of biocompatibility and as a model for comparing other materials.

Titanium and its alloys are used worldwide in surgery. Dental implants, screws and plates, prostheses, and surgical instruments are made with titanium-based metals. The favorable characteristics that make this material desirable for implantation are (a) mechanical proprieties and (b) biocompatibility. The latter has been demonstrated by in vivo studies with animal models and clinical trials over a 40-year period. However, the exact effect of titanium on cells is still not well characterized. Expression profiling by DNA microarray is a new molecular technology that allows the analysis of gene expression in a cell system. Several genes whose expression was significantly up- or downregulated in an osteoblast-like cell line (MG-63) on titanium were identified with the use of DNA microarrays containing 19,200 genes. The differentially expressed genes are associated with a broad range of functional activities, including apoptosis, vesicular transport, and structural function. It was also possible to detect some genes whose function is unknown. The data reported are, to the author's knowledge, the first genetic portrait of titanium-cell interaction. They may help to provide a better understanding of the molecular mechanisms of titanium biocompatibility and serve as a model for studying the biocompatibility of other materials., (Copyright 2003 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 66B: 341-346, 2003)

In the head and neck region, clear cell tumors are usually derived from salivary glands, odontogenic tissues, and metastasis. The World Health Organization has classified clear cell odontogenic tumor among benign tumors, but it is now recognized as a more sinister lesion, and current opinion is that it should be designated as a carcinoma. It is characterized by aggressive growth, recurrences, and metastasis. By using complementary DNA microarrays, several genes in clear cell odontogenic tumor were identified that are differentially regulated when compared with non-tumor tissue. In conclusion, the first genetic profiling of clear odontogenic carcinoma is reported. DNA microarrays can potentially help in identifying some genes whose products could be disease-specific targets for cancer therapy as well as a tool for better classifying odontogenic tumor.

Several features of the implant surface, such as composition, topography, roughness, and energy, play a relevant role in implant integration with bone. Little is known about the structural and chemical surface properties that may influence biological responses. Expression profiling by DNA microarray is a molecular technology that allows the analysis of gene expression in a cell system. By using DNA microarrays containing 19200 genes, we identified several genes whose expression was significantly down-regulated in osteoblast-like cell line MG63 on a new implant surface (titanium pull spray superficial [TPSS] surface, Oralplant, Cordenons, PN, Italy). The differentially expressed genes cover a broad range of functional activities: (1) signaling transduction, (2) translation, (3) cell cycle regulation, (4) structural and metabolic functions, and (5) apoptosis. It was also possible to detect some genes whose functions are unknown. The data reported can be relevant to better understand the role of the type of surface on the molecular mechanism of implant osseointegration and as a model for comparing other materials.

Background: Craniosynostosis syndromes, a group of connective disorders characterized by abnormalities in vault osteogenesis and premature fusion of bone sutures, are associated with point mutations in FGF receptor family members. The cellular phenotype is characterized by abnormal extracellular matrix turnover., Material and Methods: We used primary cultures of periosteal fibroblasts derived from two different craniosynostosis syndromes, the Apert and Crouzon syndromes. The FGFR2 third immunoglobulin-like domain and its flanking linker regions were analyzed for mutation. DNA microarrays containing 19,200 cDNAs were used to study the gene expression profiles of Apert and Crouzon fibroblasts. The pathologic cells were compared to wild-type human periosteal fibroblasts., Results: The P253R missense mutation and the G338R mutation were observed in Apert and Crouzon fibroblasts, respectively. The genetic profiles, as evaluated by DNA microarrays, yielded different clusters of expressed sequence tag (ESTs) expression within the experiment. Expression profiles from craniosynostosis-derived fibroblasts differ from those of wild-type fibroblasts (288 human ESTs, p< 0.01, pFDR = 0.12). Furthermore, two ESTs clusters discriminate the Crouzon from Apert fibroblasts. The differentially expressed genes cover a broad range of functional activities, including (1) bone differentiation, (2) cell-cycle regulation, (3) apoptotic stimulation, and (4) signaling transduction, cytoskeleton, and vesicular transport., Conclusions: The transcriptional program of craniosynostosis fibroblasts differs from that of wild-type fibroblasts. Expression profiles of Crouzon and Apert fibroblasts can also be distinguished by two EST expression clusters, thus hinting at a different genetic background.

Differentially expressed genes among different benign and malignant salivary gland tumors were identified by use of cDNA microarrays containing 19,000 human expressed sequence tags. Tumors were classified by using a subset of 486 genes. Benign Warthin's tumor and pleomorphic adenoma showed very distinctive gene expression patterns. One hundred and thirty-three genes differentiated the single malignant clear cell carcinoma from non-tumor salivary glands (P < 0.01), whereas only 16 genes separated it from the highly related benign pleomorphic adenoma (P < 0.01). Fifty-seven cDNAs were associated with mucoepidermoid carcinoma (P < 0.01). The identified genes might help to disclose the molecular mechanisms and processes underlying malignant salivary gland tumors.