Stereotaktilise kiiritusravi rakendamine oligometastaatilise kasvaja korral

Varem on metastaatilise kasvaja ravi keskmes olnud palliatiivne süsteemne ravi. Viimasel ajal osutatakse üha rohkem tähelepanu oligometastaatilisele haigusele, mida peetakse potentsiaalselt ravitavaks, kui lähtuda väljapakutud hüpoteesist, et vähi metastaseerumist võiks peatada varajases etapis siirdeid külvavate kloonide (oligometastaaside) hävitamisega. Tõeliseks oligometastaatiliseks haiguseks peetakse seisundit, mille korral esineb maksimaalselt kuni 5 metastaatilist kollet tuvastatud primaarse kasvaja puhul. Tänapäeval kasutatakse üksikute metastaaside eemaldamiseks kõige sagedamini kirurgilist resektsiooni. Samas on kirurgilise ravi võimalused piiratud enam kui pooltel patsientidest sõltuvalt haige üldseisundist ja kaasnevatest haigustest, metastaaside iseloomust ning asukohast. Üha populaarsemaks ja efektiivsemaks alternatiiviks oligometastaatilise haiguse ravis on muutunud stereotaktiline erinevate kehapiirkondade kiiritusravi (ingl stereotactic body radiotherapy – SBRT või ingl stereotactic ablatiive radiation therapy – SABR). SBRT ja/või SABR on täppiskiiritusravi (TKR) viisid, mille puhul kasutatakse ühe fraktsiooni kohta suurt kiirgusdoosi, fookustades selle täpselt tuumorisse ning säästes maksimaalselt ümbritsevaid kudesid.Ülevaates on tutvustatud TKRi võimalusi erinevate kasvajate algkollete ja lokalisatsiooniga oligometastaaside puhul. Eesti Arst 2017; 96(3):137–14

ADAM12 ja CILP geenide roll põlve osteoartiidi arengus

Väitekirja elektrooniline versioon ei sisalda publikatsioone.Osteoartriit (OA) on kõige levinum liigesehaigus, mille kujunemisel on oluline roll nii väliskeskkonna faktoritel kui geneetilisel eelsoodumusel. On teada, et geenid võivad mõjutada OA kulgu ja raskust, samuti ka teisi OA riskifaktoreid. Tänapäeval käsitletakse OA kõiki liigesekudesid haarava protsessina, mille kujunemisel on oluline roll põletiku komponendil. Haiguse lai levik, definitiivse ravi puudumine ning lünklik arusaam protsessi patogeneesist tekitab vajaduse üksikasjalikult uurida kandidaatgeenide seoseid haigusega nii DNA, vastava valgu kui ka RNA tasemel. Selle uurimuse eesmärkideks oli selgitada põlve OA (POA) kahe kandidaatgeeni−ADAM12 (desintegriin ja metallopeptidaasi domään 12) ja CILP (kõhre keskmise kihi proteiin)−seotust POA patogeneesi teatud aspektidega. Mõlema geeni seost POA-ga on vähe uuritud ning puuduvad andmed Eesti populatsiooni kohta. Uurimus tugines populatsioonil baseeruv kohortile (N=437) ning artroskoopiliselt ravitud patsientidele (N=91) vanuses 32−60 a. Uurimistöö käigus avastati ADAM12 seos POA riskiga geeni ja valgu tasemel. Leiti seos ADAM12 geeni polümorfismide ning radioloogilise POA-ga. POA riskiga seotud variandid erinesid meestel ja naistel. Radioloogilistest tunnustest määratles ADAM12 ainult ostefüütide tekke riski mõlemal sool. ADAM12 geeni valk-produkti ADAM12-S kontsentratsioon seerumis oli oluliselt kõrgem väljendunud radioloogilise POA-ga isikutel. Leiti korrelatsioon ADAM12 mRNA sünoviaalse ekspressiooni ja sünoviidi vahel, tugevaim seos sünoviidi tunnustest esines fibroosiga. Kõhre-spetsiifiliseks peetavat markerit CILP-i leiti sünoovias mRNA ja valgu tasemel, mis osutab võimalusele, et sünoviaalmembraan võib olla täiendavaks CILP produktsiooni allikaks. Sarnaselt ADAM12-ga leiti CILP mRNA üleekspressioon fibrootilistes proovides. CILP mRNA sünoviaalne ekspressioon oli oluliselt madalam neil isikutel, kel oli väljendunud liigespilu kitsenemine. Mõlemad geenid avaldusid soo-spetsifilist mõju varajase ja hilise radioloogilise POA riskile ning fibrogeneesile. Käesolev uuring näitab ADAM12 ja CILP geenide seost OA patogeneesi erinevate aspektidega−ADAM12 geeni osalemist luu remodeleerimise protsessides (osteofüütide teke) ning ADAM12 ja CILP geenide osalemist sünoviaalse fibroosi arenemisel.Osteoarthritis (OA) is the most common arthritic disorder, with a large number of environmental and genetic risk factors. Genetic factors have been shown to influence the dynamics and outcomes of OA, as have other OA risk factors. Currently, OA is recognised as a form of arthritis with an inflammatory component, which involves all of the joint tissues. The global burden of the disease and lack of definitive treatment, as well insufficient knowledge of several pathogenetic steps, ensure the importance of genetic research in OA. Comprehensive consideration of promising candidate genes on the mRNA and protein levels could improve our current knowledge of the disease. The aims of the present study were to perform an analysis of two OA candidate genes–ADAM12 (disintegrin and metalloproteinase domain 12) and CILP (cartilage intermediate layer protein)–on DNA-RNA-protein levels in radiographic knee OA (rKOA). The study consisted of a population-based cohort (N=437) and subjects undergoing arthroscopy (N=91), aged 32–60. The current study demonstrated that ADAM12 is associated with rKOA processes at different levels (gene and protein). Polymorphisms of the ADAM12 gene carried the risk of rKOA. In males and females rKOA risk was associated with different variants. In both genders the risk was associated only with osteophytosis. The protein product of the ADAM12 gene (ADAM12-S) was found at higher concentrations in the late stages of the disease. The expression of ADAM12 mRNA and protein in synovia was up-regulated during synovial inflammation, especially in fibrosis. CILP, which is thought to be a specific cartilage biomarker, was found in synovia at the mRNA and protein levels, suggesting that synovia may be an additional source of CILP production. Similarly to ADAM12, the synovial expression of CILP mRNA was found to be up-regulated in fibrotic samples. Moreover, CILP mRNA expression was down-regulated in subjects with advanced stages of joint space narrowing. Both genes demonstrated gender-specific effects on rKOA risk and synovial fibrogenesis. The present study establishes the association of ADAM12 and CILP genes with different aspects of KOA pathogenesis, suggesting involvement of the ADAM12 gene in bone remodelling (osteophytosis), as well the role of ADAM12 and CILP genes in the development of synovial fibrosis

Borislav Runanine as the Head Mistress (centre left), David Lichine as a cadet (centre middle), Olga Morosova (?) as a junior girl (centre right), Igor Schwezoff as the Old General (front right back to audience), and artists of the company, in Graduation ball, The Original Ballet Russe, Australian tour, His Majesty's Theatre, Melbourne, 1940 [picture] /

From: Graduation ball : ballet in one act / by David Lichine ; music by Johann Strauss ; compiled, arranged and orchestrated by Antal Dorati.; Inscription: "4L/18".; Part of the collection: Hugh P. Hall collection of photographs, 1938-1940.; Performed April - June 1940.; Choreography by David Lichine ; scenery and costumes by Alexandre Benois ; scenery executed by Nadejda Benois ; ladies' costumes executed by O. Larose and Antoinette ; male costumes executed by A. H. Leiser.; Also available in an electronic version via the Internet at: http://nla.gov.au/nla.pic-vn4174724. One of a collection of photographs taken by Hugh P. Hall of 28 ballet productions performed by the Covent Garden Russian Ballet (toured Australia 1938-1939) and the Original Ballet Russe (toured Australia 1939-1940). These are the second and third of the three Ballets Russes companies which toured Australasia between 1936 and 1940. The photographs were taken from the auditorium during a live performance in His Majesty's Theatre, Melbourne and mounted on cardboard for display purposes. For conservation and storage, the photographs have been demounted. The original arrangement of the photographs has been recorded, and details are available from the Pictures Branch of the National Library

A meta-analysis of interleukin-6 promoter polymorphisms on risk of hip and knee osteoarthritis

Objective: Interleukin-6 is a pro-inflammatory cytokine involved in the pathogenesis of osteoarthritis (OA). We investigated the role of two single nucleotide polymorphisms (SNPs) mapping to the promoter of the IL-6 gene on genetic susceptibility to hip and knee OA. Methods: The -174 G/C (rs1800795) and -597 G/A (rs1800797) SNPs, implicated in the literature in risk of hip and hand OA, were genotyped in 2511 controls, 1101 hip OA cases and 1904 knee OA cases from four cohorts from the UK and Estonia. Data were analysed in conjuntion with published data on rs1800797 from the Genetics of OA and Lifestyle study (UK) on 791 controls. 1034 knee and 997 hip OA cases and rs1800795 data on 75 hip OA cases and 96 controls from Italy. Cases included both radiographic OA only and radiographic and symptomatic OA. Fixed and random-effects meta-analysis models were tested. Results: No significant association was found with hip OA or knee OA with either SNP nor with the haplotypes formed by them. For individual SNPs the smallest P-value for hip OA was observed using a random-effects model for rs1800795 ORG allele = 1.066 (95% CI 0.89-1.28) P < 0.49, and significant heterogeneity between cohorts (I-2 = 65%, P < 0.034) was detected. For knee OA the smallest P-value was seen for rs1800797 ORA allele = 1.055 (95%CI 0.98-1.12) P < 0.18, no significant heterogeneity was observed (I-2 = 0%, P < 0.68). Conclusions: Our data do not support a role for the -174 and -597 IL-6 promoter polymorphisms in genetic susceptibility to knee or hip OA in Caucasian populations. (C) 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved

Genetic Variation in the SMAD3 Gene Is Associated With Hip and Knee Osteoarthritis

OBJECTIVE: Smad3 (or, MADH3) is a key intracellular messenger in the transforming growth factor beta signaling pathway. In mice, Smad3 deficiency accelerates growth plate chondrocyte maturation and leads to an osteoarthritis (OA)-like disease. We undertook this study to investigate the role of genetic variation in SMAD3 in the risk of large-joint OA in humans. METHODS: Ten tag single-nucleotide polymorphisms (SNPs) in the SMAD3 gene region were tested in a discovery set: 313 patients who had undergone total knee replacement, 214 patients who had undergone total hip replacement, and 520 controls from the UK. The SNP associated with both hip and knee OA was subsequently genotyped in 1,221 controls and 1,074 cases from 2 cohorts of patients with hip OA and 2,537 controls and 1,575 cases from 4 cohorts of patients with knee OA. RESULTS: A SNP (rs12901499) mapping to intron 1 of SMAD3 was associated with both knee and hip OA (P < 0.0022 and P < 0.021, respectively) in the discovery set. In all study cohorts, the major allele (G) was increased among OA patients relative to controls. A meta-analysis for knee OA yielded an odds ratio (OR) of 1.22 (95% confidence interval [95% CI] 1.12-1.34), P < 7.5 x 10(-6). For hip OA, the OR was 1.22 (95% CI 1.09-1.36), P < 4.0 x 10(-4). No evidence for heterogeneity was found (I(2) = 0%). CONCLUSION: Our data indicate that genetic variation in the SMAD3 gene is involved in the risk of both hip OA and knee OA in European populations, confirming the results from animal models on the potential importance of this molecule in the pathogenesis of OA

Osteoarthritis of the Knee in European-Descent Populations

Abstract Osteoarthritis (OA) is the most common form of arthritis and a major cause of disability. This study evaluates the association in Caucasian populations of two single nucleotide polymorphisms (SNPs) mapping to the Human Leukocyte Antigen (HLA) region and deriving from a genome wide association scan (GWAS) of knee OA in Japanese populations. The frequencies for rs10947262 were compared in 36,408 controls and 5,749 knee OA cases from European-descent populations. rs7775228 was tested in 32,823 controls and 1,837 knee OA cases of European descent. The risk (major) allele at rs10947262 in Caucasian samples was not significantly associated with an odds ratio (OR) = 1.07 (95%CI 0.94 -1.21; p = 0.28). For rs7775228 the metaanalysis resulted in OR = 0.94 (95%CI 0.81-1.09; p = 0.42) for the allele associated with risk in the Japanese GWAS. In Japanese individuals these two SNPs are in strong linkage disequilibrium (LD) (r 2 = 0.86) with the HLA class II haplotype DRB1*1502 DQA1*0103 DQB1*0601 (frequency 8%). In Caucasian and Chinese samples, using imputed data, these SNPs appear not to be in LD with that haplotype (r 2 ,0.07). The rs10947262 and rs7775228 variants are not associated with risk of knee OA in European descent populations and they do not appear tag the same HLA class II haplotype as they do in Japanese individuals

The impact of regulations on firms: a case study of the biotech industry

Osteoarthritis (OA) is the most common form of arthritis and a major cause of disability. This study evaluates the association in Caucasian populations of two single nucleotide polymorphisms (SNPs) mapping to the Human Leukocyte Antigen (HLA) region and deriving from a genome wide association scan (GWAS) of knee OA in Japanese populations. The frequencies for rs10947262 were compared in 36,408 controls and 5,749 knee OA cases from European-descent populations. rs7775228 was tested in 32,823 controls and 1,837 knee OA cases of European descent. The risk (major) allele at rs10947262 in Caucasian samples was not significantly associated with an odds ratio (OR) = 1.07 (95%CI 0.94 -1.21; p = 0.28). For rs7775228 the metaanalysis resulted in OR = 0.94 (95%CI 0.81-1.09; p = 0.42) for the allele associated with risk in the Japanese GWAS. In Japanese individuals these two SNPs are in strong linkage disequilibrium (LD) (r2 = 0.86) with the HLA class II haplotype DRB1*1502 DQA1*0103 DQB1*0601 (frequency 8%). In Caucasian and Chinese samples, using imputed data, these SNPs appear not to be in LD with that haplotype (r2,0.07). The rs10947262 and rs7775228 variants are not associated with risk of knee OA in European descent populations and they do not appear tag the same HLA class II haplotype as they do in Japanese individuals

Meta-analysis of genetic association between two HLA SNPs and knee OA.

<p>Forest plot of study-specific estimates and random-effects summary effect size and 95% confidence intervals (95%CIs) for the genetic association with knee OA of (<b>A</b>) the major allele (T) at rs7775228 in three published studies and the deCODE case-control study (<b>B</b>) the major allele (C) at rs10947262 in three published studies and seven additional European studies. Square sizes are proportional to the number of cases in each study.</p