Correlation of biological markers with response to preoperative radiotherapy in locally advanced noninflamatory breast cancer

terapiji lokalno odmaklog karcinoma dojke (LOKD) preoperativna radioterapija (PRT) je u današnje vreme indikovana nakon primarne (neoadjuvantne) hemioterapije (PHT) u slučaju da nije postignuta resektabilnost tumora. Pre uvodjenja neoadjuvantne hemioterapije, PRT se mnogo češće koristila kao jedini neoadjuvantni pristup za inicijalno inoperabilne tumore, u cilju smanjenja tumorskog volumena i omogućavanja radikalne hirurgije. Cilj ove analize je evaluacija tumorskog odgovora i dugoročnog ishoda bolesti kod pacijenata tretiranih samo PRT, bez uticaja sistemske terapije, i procena povezanosti bioloških markera sa odgovorom na PRT. Metod: U periodu od 1997-2000.godine 134 bolesnica sa neinflamatornim LOKD stadijuma IIIA i IIIB tretirano je preoperativnom RT. Tumorska doza je bila 45 Gy u 15 frakcija (3 Gy po frakciji) naizmenično svakog drugog dana na regiju dojke i regionalnih limfatika u toku 6 nedelja. Šest nedelja po završenoj RT, učinjena je radikalna mastektomija kod svih bolesnica i potom primenjena adjuvantna terapija (hemioterapija i/ili hormonska terapija) po tadašnjem protokolu. Ishod bolesti je procenjivan na osnovu ukupnog preživljavanja (OS) i preživljavanja bez znakova bolesti (DFS). Krive preživljavanja (OS i DFS) su procenjivane korišćenjem Kaplan-Meier metode i univarijantne statističke analize korišćenjem Log-Rank testa u cilju procene razlike izmedju analiziranih grupa. Status hormonskih receptora ER i PgR, HER-2 status i Ki-67 su analizirani imunohistohemijskim metodama na uzorku biopsiranog tumora i uzorku na mastektomiji. Merenje genske ekspresije vršeno je iz parafinskih uzoraka tumorskog tkiva Microarray analizom. Rezultati: Medijana praćenja iznosila je 74 meseca (ranga 4-216). Klinički odgovor tumora na PRT zabeležen je kod 77.6% bolesnica. Klinički kompletan odgovor tumora (cCR) postignut je kod 21.6% bolesnica, dok je patohistološki kompletan odgovor (pCR) u dojci registrovan kod 15% bolesnica. Od toga 10/134 (7.5%) je ostvario totalni pCR (bez invazivnog tumora u dojci i bez pozitivnih limfnih čvorova u aksili). Petogodišnje i l0-godišnje OS je bilo 55.1% i 37.8%, dok je 5-godišnje i 10-godišnje DFS bilo 39.2% i 27%. Bolesnice koje su postigle cCR su imale statistički duže OS u poredjenju sa onima sa cPR i cSD (Log-Rank test, p=0.038). Slično je i DFS bolesnica sa cCR bilo duže u odnosu na cPR i cSD, mada razlika nije bila statistčki značajna. Analizom bioloških markera pokazano je da pacijenti sa luminal A tumorima imaju bolje preživljavanje u odnosu na ostale podtipove, dok trostruko negativni tumori imaju najbolji odgovor na PRT (40% pCR i pNCR). Analiza genske ekspresije primarnog tumora je pokazala da su tri gena (APOA1, MAP3K4 i MMPM) značajno različito eksprimirana izmedju RT-rezistentnih i RT-responzivnih tumora. Zaključak: Naši rezultai su pokazali da lokalna kontrola pacijenata sa LOKD tretiranih preoperativnom RT i radikalnom mastektomijom je komparabilna sa rezultatima prikazanim u literaturi. Kompletan patohistološki odgovor (pCR) na PRT izdvaja grupu bolesnica koje naginju ka boljem OS i DFS.In the treatment of locally advanced breast cancer (LABC) preoperative radiotherapy (PRT) today is indicated after primary (neoadjuvant) chemotherapy (PCT) if resectability of tumor was not achieved. Before the introduction of PCT in treatment strategy, PRT was more frequently used as the sole neoadjuvant approach for initially inoperable tumors, in order to reduce tumor volume and reach radical surgery. The purpose of this analysis was to evaluate the tumor response and long-term outcome at patients treated with only PRT, without influence of systemic therapy, and to assess the relationship of biological markers with response to PRT. Method: Between 1997 and 2000, 134 patients with non-inflammatory LABC stage IIIA and IIIB were treated with PRT. The tumor dose was 45 Gy in 15 fractions (3 Gy per fraction) every second day to the breast and to regional lymph nodes over 6 weeks. Radical mastectomy was performed 6 weeks after PRT to all patients and adjuvant systemic therapy was administered as per protocol. The measure of disease outcome were overall survival (OS) and disease-free survival (DFS). Survival and DFS curves were estimated using the Kaplan-Meier method and univariate statistical analysis by Log rank test was used to assess the difference in time to event (OS/DFS) between the analyzed groups. The hormone receptor status of ER and PgR, HER-2 status and Ki-67 were assessed by immunohistochemistry on the biopsy and mastectomy specimens. Gene expression profiles were established using micro-array analysis in a formalin-fixed paraffin-embedded (FFPE) tumor samples. Results: Median follow-up was 74 months (range 4-216 months). An objective clinical tumor response after preoperative RT was observed in 77.6% of patients. Clinical complete tumor response (cCR) was achieved in 21.6% of patients. Pathological CR in the breast was achieved in 15% of patients. Among them 10/134 (7.5%) had total pCR (no invasive tumor in breast associated with no involved regional axillary lymph nodes. The 5 and 10-year OS were 55.1% and 37.8% respectively. The 5 and 10-year DFS were 39.2% and 27% respectively. Patients who achieved cCR had significantly longer OS in comparison with patients achieving cPR and cSD. Similarly, DFS of patients in cCR group was longer compered to patients with cPR and cSD, although it did not reach statistical significance. Analysis of biological markers has shown that patients with luminal A tumors had better OS than other subtypes, but triple-negative breast cancers (TNBC) had the best response to PRT (40% of pCR and pNCR). Gene expression analysis of primary tumor has shown that three genes (APOA1, MAP3K4 and MMPM) were significantly differentially expressed between RT-resistant and RT-responsive tumors. Conclusion: Our results showed that local control in LABC patients achieved by primary PRT, followed by radical mastectomy was comparable with the results reported in literature. Complete pathologic response to PRT identified a subgroup of patents with a trend toward better DFS and OS

Uticaj mehano-hemijske aktivacije flotacijske jalovine na stepen izdvajanja korisnih komponenti

The presented results refer to the investigation of effect the mechanical-chemical activation of flotation tailings on copper, iron and sulfur leaching degree in the sulfuric-chloride solution with the addition of H2O2 as oxidant. A sample of the Bor flotation tailings (BFT) from the old Bor flotation tailing dump consists of pyrite and tailings as the main components, and is activated in a dry process of the vibro mill with (BFT1) and without (BFT2) addition of NaOH as the chemical reagent. Using the dry magnetic separation in thee high-gradient magnetic separator Sala, the samples were separated into magnetic and non-magnetic fraction, BFT MF and BFT NMF, respectively. Leaching of various treated samples showed that the highest level of copper leaching (98.7 wt %), was obtained for BFJ2 MF sample while the leaching degree of Fe and S was higher in non-magnetic fractions, up to 92.46 wt % in BFT1 NMF sample for Fe and 80.62 wt % for S in BFT2 NMF sample.Prikazani rezultati odnose se na ispitivanje uticaja mehano-hemijske aktivacije flotacijske jalovine na stepen izluženja bakra, gvožđa i sumpora u sumporno-hloridnom rastvoru uz dodatak H2O2 kao oksidansa. Uzorak borske flotacijske jalovine (BFJ) sa lokacije starog borskog flotacijskog jalovišta sadrži 23% pirita i 75,23% jalovine kao osnovne komponente, a aktiviran je suvim postupkom u vibro mlinu bez i sa dodatkom NaOH kao hemijskog reagensa, uzorci BFJ1 i BFJ2, respektivno. Suvom magnetnom separacijom u visokogradijentnom magnetnom separatoru 'Sala', uzorci su razdvojeni na magnetičnu i nemagnetičnu frakciju, BFJ MF i BFJ NMF, respektivno. Luženje različito tretiranih uzoraka pokazalo je da je najviši stepen izluženja bakra, 98,7 %, postignut kod uzorka BFJ2 MF dok je stepen izluženja Fe i S viši kod nemagnetičnih frakcija, i kreće se do 92,46 % kod uzorka BFJ1 NMF za Fe i 80,62 % za S iz uzorka BFJ2 NMF

Variable neighbourhood decomposition search for 0-1 mixed integer programs

In this paper we propose a new hybrid heuristic for solving 0-1 mixed integer programs based on the principle of variable neighbourhood decomposition search. It combines variable neighbourhood search with a general-purpose CPLEX MIP solver. We perform systematic hard variable fixing (or diving) following the variable neighbourhood search rules. The variables to be fixed are chosen according to their distance from the corresponding linear relaxation solution values. If there is an improvement, variable neighbourhood descent branching is performed as the local search in the whole solution space. Numerical experiments have proven that exploiting boundary effects in this way considerably improves solution quality. With our approach, we have managed to improve the best known published results for 8 out of 29 instances from a well-known class of very di±cult MIP problems. Moreover, computational results show that our method outperforms the CPLEX MIP solver, as well as three other recent most successful MIP solution methods

Selective non-catalytic denitrification of biomass combustion flue gases (synthetic mixture)

Despite many benefits of agricultural biomass utilization as an energy source, there are certain disadvantages such as the possible high emission of NOx. The NOx emission represents one of the key challenges for agricultural biomass use as a fuel. The experimental denitrification chamber was used to evaluate the impact of initial NO content, NH3:NO molar ratio, flue gas temperature, and the temperature difference between two denitrification chamber sections on NOx reduction using ammonia aqueous solution. The optimization of experimental conditions was done in the NO concentration range from 200-800 ppm, NH3:NO molar ratios from 0.31-3 and second chamber section temperature range from 770-67°C. The denitrification process under controlled conditions is the starting point for the optimization of the secondary denitrification technique of selective non-catalytic reduction SNCR process on real-scale plants combusting biomass or any other fuels with increased NOx emission

New variants of variable neighbourhood search for 0-1 mixed integer programming and clustering

Many real-world optimisation problems are discrete in nature. Although recent rapid developments in computer technologies are steadily increasing the speed of computations, the size of an instance of a hard discrete optimisation problem solvable in prescribed time does not increase linearly with the computer speed. This calls for the development of new solution methodologies for solving larger instances in shorter time. Furthermore, large instances of discrete optimisation problems are normally impossible to solve to optimality within a reasonable computational time/space and can only be tackled with a heuristic approach. In this thesis the development of so called matheuristics, the heuristics which are based on the mathematical formulation of the problem, is studied and employed within the variable neighbourhood search framework. Some new variants of the variable neighbourhood searchmetaheuristic itself are suggested, which naturally emerge from exploiting the information from the mathematical programming formulation of the problem. However, those variants may also be applied to problems described by the combinatorial formulation. A unifying perspective on modern advances in local search-based metaheuristics, a so called hyper-reactive approach, is also proposed. Two NP-hard discrete optimisation problems are considered: 0-1 mixed integer programming and clustering with application to colour image quantisation. Several new heuristics for 0-1 mixed integer programming problem are developed, based on the principle of variable neighbourhood search. One set of proposed heuristics consists of improvement heuristics, which attempt to find high-quality near-optimal solutions starting from a given feasible solution. Another set consists of constructive heuristics, which attempt to find initial feasible solutions for 0-1 mixed integer programs. Finally, some variable neighbourhood search based clustering techniques are applied for solving the colour image quantisation problem. All new methods presented are compared to other algorithms recommended in literature and a comprehensive performance analysis is provided. Computational results show that the methods proposed either outperform the existing state-of-the-art methods for the problems observed, or provide comparable results. The theory and algorithms presented in this thesis indicate that hybridisation of the CPLEX MIP solver and the VNS metaheuristic can be very effective for solving large instances of the 0-1 mixed integer programming problem. More generally, the results presented in this thesis suggest that hybridisation of exact (commercial) integer programming solvers and some metaheuristic methods is of high interest and such combinations deserve further practical and theoretical investigation. Results also show that VNS can be successfully applied to solving a colour image quantisation problem.EThOS - Electronic Theses Online ServiceMathematical Institute, Serbian Academy of Sciences and ArtsGBUnited Kingdo

Bioaktivne komponente u funkciji oplemenjivanja industrijskog paradajza

Selection of tomato lines for industrial use regarding their nutritional value is a potential that will reflect in the final product obtained from tomato fruits. At the same time, technological process of preparation of tomato juice (100 °C), as well as hot air drying, was studied in order to establish an optimal technological process that is the least disrupting for the natural potential of nutrients contained in fresh fruits. The research was performed on 6 lines and one variety of industrial tomato. The content of vitamin C, vitamin E, lycopene, β-carotene, phenols, flavonoids, dry matter and total antioxidative capacity was studied by applying standard methods for determination of the level of these parameters. Grouping was performed according to traits of average carotenoid content (lycopene, β-carotene), vitamin C, vitamin E, phenols, flavonoids, dry matter and total antioxidative capacity in tomato fruit, by applying PCA. The first two principle components were responsible for 77.18 % of total variability of researched samples. The impact of other five components was low and they were responsible for 22.18 % of the variability. Antioxidative activity was best preserved after finishing, through small losses of lycopene and β-carotene. Losses of vitamin C, vitamin E, phenols and flavonoids during thermal processing were great, mostly in juice, while in dried product, these losses were lower. Nutrient losses were in function of temperature height that the fruits were exposed to during the thermal processing. Genotypes SPRZ and SPSM were marked as the best.Selekcija linija paradajza namenjenog industrijskoj preradi prema osobinama koje definišu njihovu nutritivnu vrednost predstavljaju potencijal koji će se reflektovati u proizvodu dobijenom od plodova paradajza. U isto vreme ispitan je i tehnološki proces pripreme soka paradajza (100 °C) kao i sušenje plodova na toplom vazduhu, kako bi se utvrdio optimalni tehnološki proces koji najmanje narušava prirodni potencijal nutrijenata sadržanih u svežim plodovima. Ispitivanje je sprovedeno na 6 linija i jednoj sorti industrijskog paradajza gde su ispitani sadržaj vitamina C, vitamina E, likopina, β-carotina, fenola, flavonoida, suve materije i ukupni antioksidativni kapacitet, standardnim metodama za utvrđivanje sadržaja ovih parametara. Grupisanje je izvršeno prema osobinama prosečnog sadržaja karetinoida (likopen, β-karoten), vitamina C, vitamina E, fenola, flavonoida, suve materije i ukupnog antioksidatinog kapaciteta u plodu paradajza, pomoću PCA analize. Prve dve principle komponente odgovorne su za 77,18 % ukupne varijabilnosti ispitivanih uzoraka. Uticaj ostalih pet komponenti je mali i one su odgovorne za 22,18 % varijabilnosti. Antioksidativna aktivnost je najbolje očuvana posle dorade kroz male gubitke likopina i β-karotina posle dorade. Gubici vitamina C, vitamina E, fenola, flavonoida pri termičkoj obradi su veliki i to najviše u soku, dok kod sušenog proizvoda ti gubici su nešto manji. Gubici nutrijenata su u funkciji visine temperature kojima su plodovi bili izlagani pri termičkoj obradi. Kao najbolji genotipovi ocenjeni su SPRZ i SPSM

Uticaj termičke obrade plodova paradajza na antioksidativnu aktivnost, sadržaj vitamina E, suve materije i ukupnih šećera

The objective of this study was the determination of total antioxidant activity, contents of vitamin E, sugar and total dry matter in fresh and thermally processed (dried and juiced) tomato fruits of different selected tomato lines with the aim to establish the nutritive profile and distinguish superior genotypes in order to obtain high-quality final product with more benefit to human health. Content of vitamin E, total antioxidant activity, dry matter and total sugars, in fresh and dried fruits (dried in parallel hot air dryer at 60 °C, until the final product reached the moisture lower than 10% and in tomato juice pasteurized at 100 °C, for 7 minutes) was studied. Comparative trial with 7 genotypes: one commercial variety (SP-109) and 6 selected high inbreeding generation lines (SPP, SPSM, SPRZ, SPRM-20, S-60 and SPO), was set up. Genotype SPRZ had the highest vitamin E content and total antioxidant capacity, both in fresh fruit and after the treatments. Thermal processing by drying at 60°C and pasteurization of tomato changed the level of total sugar and dry matter content. Total antioxidant activity decreased by drying, comparing to fresh fruit while the level of vitamin E decreased in juice pasteurized at high temperature (100 °C). .Cilj istraživanja je određivanje ukupne antioksidativne aktivnosti, sadržaja vitamina E, sadržaja šećera i ukupne suve materije u svežim i termički obrađenim (sušeni plodovi i sok) plodovima različitih selekcionih linija paradajza, sa ciljem utvrđivanja nutritivnog kvaliteta i izdvajanja superiornih genotipova, čijom preradom bi se dobio kvalitetniji krajnji proizvod sa pozitivnim dejstvom na ljudsko zdravlje. Ispitivani su sadržaj vitamina E, ukupna antioksidativna aktivnost, suva materija, i ukupni sadržaj šećera, kod svežih plodova, sušenih plodova (sušenje toplim vazduhom na 60 °C, do konačne vlage uzorka manje od 10%) i soka paradajza (pasterizacijom na 100 °C, u trajanju od 7 minuta). Izveden je komparativni ogled sa 7 genotipova, jedna komercijalna sorta (SP-109) i 6 selekcionisanih linija (SPP, SPSM, SPRZ, SPRM-20, S-60 I SPO) visokih generacija inbridinga. Termička obrada plodova paradajza (sušenjem na 60 °C) i pravljenjem soka dovodi do promene ukupnog sadržaja šećera i sadržaja ukupne suve materije. Ispitivanjem ukupne antioksidativne aktivnosti utvrđeno je da se ona gubi sušenjem u odnosu na svež plod, a sadržaj vitamina E se smanjio u soku koji je dobijen obradom na višim temperaturama (100 °C). Genotip SPRZ imao je najviše vrednosti za sadržaj vitamina E i ukupan antioksidativni kapacitet kako u svežem stanju tako i nakon primenjene obrade. Izborom superiornih genotipova i akumulacijom nutrijenata kroz oplemenjivačke programe, može se poboljšati kvalitet krajnjeg proizvoda i postići dobijanje prerađevina sa većim pozitivnim uticajem na zdravlje ljudi

Način nasleđivanja indeksa oblika lukovice crnog luka (Allium cepa L.)

Onion (Allium cepa L.) is a very important and widespread vegetable crop. Bulb shape index is a very significant biological and commercial trait. Bulb shape impacts the price, processing, resistance to diseases, etc., which is the reason why it is a very important economical trait. Success of the breeding process depends on genetic determination of the traits that were targeted in the selection process. In order to assess the genetic determination of bulb shape index, the trial was set up in the random block system with five replications, with diallel crossing without reciprocals. Bulb shape index in F1 generation was from flat-round to oval shaped. The most common heredity mode of the bulb shape index was superdomination. The highest value of GCA for shape index was found in 'Makoi bronzi', which was the indicator of the best combining abilities. The highest SCA in F1 and F2 generation was found in the hybrid 'Makoi bronzi' x 'AC 101'.Crni luk (Allium cepa L.) je izuzetno važna i široko raspostranjena povrtarska vrsta. Indeks oblika lukovice crnog luka predstavlja veoma značajno biološko i tržišno svojstvo. Oblik lukovica ima uticaja na tržišnu cenu crnog luka, proces dorade, otpotnost na bolesti, itd. Zbog ovoga, indeks oblika se ubraja u važnu ekonomsku osobinu lukovice crnog luka. Genetska determinisanost osobine utiče na uspešnost procesa selekcije. Kako bi utvrdili genetsku determinisanost indeksa oblika lukovice, postavljen je ogled po slučajnom blok sistemu u pet ponavljanja. Primenjen je metod dialelnog ukrštanja bez recipročnog. Posmatrajući hibridne kombinacije Fi generacije može se uočiti da se njihov indeks oblika lukovice kretao od pljosnato-okruglog do ovalnog. Najzastupljeniji način nasleđivanja indeksa oblika lukovice u ovom istraživanju je super dominacija. Najveću vrednost OKS za indeks oblika imala je linija 'Makoi bronzi'. Najvišu vrednost za PKS u F1 i F2 generaciji imao je hibrid dobijen ukrštanjem linije 'Makoi bronzi' x 'AC 101'

Uticaj mehano-hemijske aktivacije flotacijske jalovine na stepen izdvajanja korisnih komponenti

The presented results refer to the investigation of effect the mechanical-chemical activation of flotation tailings on copper, iron and sulfur leaching degree in the sulfuric-chloride solution with the addition of H2O2 as oxidant. A sample of the Bor flotation tailings (BFT) from the old Bor flotation tailing dump consists of pyrite and tailings as the main components, and is activated in a dry process of the vibro mill with (BFT1) and without (BFT2) addition of NaOH as the chemical reagent. Using the dry magnetic separation in thee high-gradient magnetic separator Sala, the samples were separated into magnetic and non-magnetic fraction, BFT MF and BFT NMF, respectively. Leaching of various treated samples showed that the highest level of copper leaching (98.7 wt %), was obtained for BFJ2 MF sample while the leaching degree of Fe and S was higher in non-magnetic fractions, up to 92.46 wt % in BFT1 NMF sample for Fe and 80.62 wt % for S in BFT2 NMF sample.Prikazani rezultati odnose se na ispitivanje uticaja mehano-hemijske aktivacije flotacijske jalovine na stepen izluženja bakra, gvožđa i sumpora u sumporno-hloridnom rastvoru uz dodatak H2O2 kao oksidansa. Uzorak borske flotacijske jalovine (BFJ) sa lokacije starog borskog flotacijskog jalovišta sadrži 23% pirita i 75,23% jalovine kao osnovne komponente, a aktiviran je suvim postupkom u vibro mlinu bez i sa dodatkom NaOH kao hemijskog reagensa, uzorci BFJ1 i BFJ2, respektivno. Suvom magnetnom separacijom u visokogradijentnom magnetnom separatoru 'Sala', uzorci su razdvojeni na magnetičnu i nemagnetičnu frakciju, BFJ MF i BFJ NMF, respektivno. Luženje različito tretiranih uzoraka pokazalo je da je najviši stepen izluženja bakra, 98,7 %, postignut kod uzorka BFJ2 MF dok je stepen izluženja Fe i S viši kod nemagnetičnih frakcija, i kreće se do 92,46 % kod uzorka BFJ1 NMF za Fe i 80,62 % za S iz uzorka BFJ2 NMF

Polycyclic aromatic hydrocarbons emission from cigar burner combustion system and comparison of their content in fly ashes

Agricultural biomass is considered a preferred RES in Serbia because of its availability and suitability to limit the use of fossil fuel resources and reduce GHG emissions. Therefore, constant work has been done to develop technologies that enable its utilization for energy purposes. As an example of these efforts, in the Agricultural Corporation PKB, the soybean straw cigarette-type combustion system has been applied for greenhouse heating for over a decade. However, many volatile and semivolatile organic compounds are emitted directly into the atmosphere or concentrated in ash particles during agricultural biomass combustion. Since some of the emitted compounds, such as polycyclic aromatic hydrocarbons (PAHs), are toxic, monitoring their concentrations in fly ash is recommended. Literature data regarding PAHs content in agricultural biomass ashes are insubstantial, especially in Serbia. For that purpose, PAHs contents in the cyclone and stack fly ashes of soybean straw were investigated and compared. In addition, the emission factors, toxicity, carcinogenicity and benzo[a]pyrene equivalence concentrations were determined and used to estimate the potential environmental impact of these ashes. As a result, stack ash has been shown to have a higher potential environmental risk than cyclone ash. Hence, an assessment of using soybean straw as a feed fuel in a real cigarette-type combustion plant regarding PAHs emission is given. These results provide important information for optimizing combustion conditions and assisting the local entities in managing air pollution and control policies in Serbia