Molecular interactions between childhood acute lymphoblastic leukaemia cells and the bone marrow microenvironment

Acute lymphoblastic leukaemia (ALL) is the most common cause from death of disease in children. Whilst cure rates over the last 30 years have drastically improved, the children that do go on and relapse have a very poor prognosis. Additionally, the ones that do survive can have significant long term side effects from existing treatments. Understanding the molecular mechanisms of the relationship between leukaemia and its microenvironment is essential for the identification of novel targets for treatment and/or the manipulation of existing treatments. The role that vascular endothelial growth factor (VEGF), an integral component of both neovascularisation and normal haematopoiesis, plays in the progression and invasiveness of solid tumours is well established. However, its function in haematological malignancies has been a more recent and thus less considered observation. Human leukaemia cells secrete VEGF, which may act in a paracrine manner with the bone marrow microenvironment to promote the survival and proliferation of leukaemia cells. In addition to VEGF being produced by leukaemias, it also increases vascularity in the bone marrow and lymph nodes of patients. Our previous work has established a panel of 10 childhood acute lymphoblastic leukaemia xenografts from patient biopsies in NOD/SCID mice. Several of these secrete VEGF, and express the FMS-like tyrosine kinase-3 (FLT-3). FLT 3, a receptor tyrosine kinase (RTK), and its ligand, play an essential role in regulating normal haematopoiesis. This thesis builds on the previous work by examining the relationship between VEGF and FLT 3, two widely, yet independently studied molecules in leukaemia, with the aberrant expression of either having adverse outcomes for patients. The results show that the high expression and activation of FLT 3, significantly increases the secretion VEGF. To assess whether VEGF secretion is triggered by FLT-3 signalling, we measured VEGF in the absence and presence of a class III receptor tyrosine kinase (RTK) inhibitor (SU11657), humanised anti-FLT 3 blocking antibodies as well as decreasing the receptors with siRNA. All of these manipulations were able to decrease the secretion of VEGF in leukaemia cells. To further investigate this relationship, we examined the phosphorylation status of FLT-3 and the downstream signalling pathway. Our results indicate that FLT 3 signalling may be an important factor in the induction of VEGF secretion in a sub-type of leukaemia cells and in turn, VEGF secretion can be attenuated by an FLT-3 specific inhibitor. Two separate microarray studies were also used to assess simultaneous gene expressions between the leukaemia and bone marrow microenvironment, and to examine the effects of FL on ALL xenograft cells. The results of the microarray studies confirm the previously observed results regarding the manipulation of the microenvironment by the leukaemic cells. Inhibition of the FLT-3/VEGF pathway may disrupt paracrine signalling between leukaemia cells and the bone marrow microenvironment, and future studies into how this disruption may influence leukaemia cell responses to conventional chemotherapy are warranted

Entirely fresh influences in Edwardian Wildeana: queerness in Mary Elizabeth Braddon's The Rose of Life (1905) and Julia Frankau's The Sphinx's Lawyer (1906)

Whereas Edwardian male-authored Wildeana tends to represent the Wildean character as a solipsistic bachelor, whose tarnished reputation could affect only his bachelor friends, Mary Elizabeth Braddon’s The Rose of Life (1905) and Julia Frankau’s The Sphinx’s Lawyer (1906) place the Wildean character within the family unit. This allows them to examine the consequences the character’s legal prosecution and stigmatisation could have on his wife. Braddon’s and Frankau’s novels shift the focus from homoeroticism and homosexuality to the catalysing role male influence plays in the development of innate queerness. At the same time, they critically engage with the contemporary belief that female influence might “cure” queerness. Braddon and Frankau avoid demonising and/or oversimplifying the Wildean character’s feelings and note that queerness and the family are by no means oppositional or antithetical units. To achieve this effect, they invariably sacrifice women’s happiness, which allows us to read their novels as more anti-feminist than anti-queer

Oral Health in 12- and 15-Year-Old Children in Serbia: A National Pathfinder Study.

The aim of the paper is to present the oral health profile of 12- and 15-year-old schoolchildren in Serbia. Basic Methods for Oral Health Surveys of the WHO were implemented to record: Decayed, Missing, and Filled Teeth/Surfaces Index (DMFT/DMFS), gingival bleeding, enamel fluorosis and other structural anomalies, dental erosion, dental trauma, and oral mucosal lesions. In addition, Silness and Löe plaque index and orthodontic status were assessed. A total of 36% of 12-year-olds and 22% of 15-year-olds in Serbia were caries-free. The mean DMFT was 2.32 ± 2.69 for 12-year-olds and 4.09 ± 3.81 for 15-year-olds. DMFT was made up largely by the decayed component. Gingival bleeding was present in 26% of examined 12-year-old and 18% of 15-year-old children. Dental plaque was observed in 63% of both 12- and 15-year-olds. Fluorosis, structural anomalies, dental erosion, dental trauma, and oral mucosal lesion were rarely detected. Low prevalence of malocclusions was found. Oral disease is still a common public health problem among schoolchildren in Serbia. A significant increase in the prevalence of caries disease between 12- and 15-year-old groups implies that preventive care for adolescents requires special attention. Corrective actions and reforms to the current school-based oral health prevention program are needed to further improve oral health in Serbian children

Path Planning with Potential Field-Based Obstacle Avoidance in a 3D Environment by an Unmanned Aerial Vehicle

In this paper we address the problem of path planning in an unknown environment with an aerial robot. The main goal is to safely follow the planned trajectory by avoiding obstacles. The proposed approach is suitable for aerial vehicles equipped with 3D sensors, such as LiDARs. It performs obstacle avoidance in real time and on an on-board computer. We present a novel algorithm based on the conventional Artifcial Potential Field (APF) that corrects the planned trajectory to avoid obstacles. To this end, our modifed algorithm uses a rotation-based component to avoid local minima. The smooth trajectory following, achieved with the MPC tracker, allows us to quickly change and re-plan the UAV trajectory. Comparative experiments in simulation have shown that our approach solves local minima problems in trajectory planning and generates more effcient paths to avoid potential collisions with static obstacles compared to the original APF method

Molecular docking study on the interaction of Rhodopsin-like receptor with tetra-coordinated gold(III) complex

The pharmacologic properties of gold compounds have been known since the end of the 19th century. In the last decade, gold complexes have received increased attention due to the variety of their applications. Rhodopsin-like receptors are a family of proteins that belong to the largest group of G protein-coupled receptors (GPCRs). In this paper, the molecular interactions between active binding sites of the Rhodopsin-like receptor (RLR) and synthesized gold(III) complex ([Au(DPP)Cl2]+ where DPP=4,7-diphenyl-1,10-phenanthroline) were investigated by molecular docking simulations. The crystal structure of investigated receptor RLR (PDB ID: 4A4M) was extracted from RCSB Protein Data Bank in PDB format. The native bound ligand (11-cis-retinal) was extracted from receptor and binding pocket analysis was performed. Re-docking was performed with the gold(III) complex to generate the same docking pose as found in co-crystallized form of receptor. The binding energy of gold(III) complex to RLR was found to be -35.35 kJ/mol, as opposed to 11-cis-retinal which of about - 40.5 kJ/mol. The obtained results of revealed that gold(III) complex binds at the same binding pockets to RLR, as well as native bound ligand, by weak non-covalent interactions. The most prominent interactions are hydrogen bonds, alkyl-π, and π-π interactions. The preliminary results suggest that gold(III) complex showed good binding affinity against RLR, as well as native bound ligand, 11-cisretinal, as evident from the free binding energy (ΔGbind in kJ/mol).The authors are grateful to the Ministry of Education, Science and Technological Development of the Republic of Serbia (Agreement No. 451-03-9/2021-14/200378 and Agreement No. 451-03-68/2021-14/200122) for financial supportPublishe

The impact of intellectual capital on ROA as a significant indicator of financial performance

In the modern business, organizations that recognize the value of intellectual resources and incorporate them into their business strategy have a greater chance of long-term success. Through continuous learning, employee development and establishing strong relationships, organizations can improve their competitive position in the market. In this regard, the aim of the paper is to examine the impact of intellectual capital, i.e., its components of human, structural and relational capital, on ROA as a significant indicator of financial performance. For the preparation of the paper, secondary data were used, which were processed with the help of the VAIC method, and then the obtained results were further analyzed using the IBM SPSS program. HCE was found to affect ROA, while SCE and CEE did not. The results of this research contribute to companies to adequately create a business strategy that contains an incorporated ratio of intellectual capital components, with an emphasis on human capital, which is the basis for the success and progress of organizations in the knowledge economy

CD19 expression in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia pre- and post-treatment with blinatumomab.

AbstractBlinatumomab is a BiTE® (bispecific T‐cell engager) immuno‐oncology therapy, which has demonstrated significant activity in patients with relapsed or refractory B‐cell precursor acute lymphoblastic leukemia (R/R B‐ALL); however, a subset of patients relapse. Monitoring expression of cluster of differentiation (CD)19 in relapsed patients is critical to inform sequencing of subsequent therapies. The expression of CD19 in 59 pediatric patients with R/R B‐ALL was analyzed on the day of diagnosis of R/R B‐ALL and on days 15 and 29 of cycle 1 of blinatumomab. Most patients treated with one cycle of blinatumomab retained expression of CD19, and would therefore be eligible for subsequent anti‐CD19 CAR T‐cell therapy

Kondiciono stanje riba, orada (sparus aurata) i brancin (dicentrarchus labrax), sa farme u Bokokotorskom zalivu (jugoistočni Jadran)

U ovom istraživanju obrađeno je 210 jedinki orade (Sparus aurata Linnaeus, 1758) i 210 jedinki brancina (Dicentrarchus labrax Linnaeus, 1758) sa uzgajališta COGIMAR koje se nalazi na lokaciji Ljuta u Bokokotorskom zalivu. Istraživanja su započeta u decembru mesecu 2014. godine i u ovom radu biće predstavljeni preliminarni podaci o dužinsko-težinskom odnosu i kondicionom faktoru ovih vrsta. Totalna dužina (TL) jedinki orade u uzorku kretala se od 19,9 do 31,1 cm, sa prosečnom vrednošću od 28,1 ± 1,8 cm (prosečna dužina ± standardna devijacija, SD), dok se raspon ukupnih težina kretao od 130 do 485 g, sa prosečnom vrednošću od 337,56 ± 55,75 g (prosečna dužina ± SD). Kod brancina totalna dužina jedinki u uzorku kretala se od 20,8 do 54 cm, sa prosečnom vrednošću od 33,7 ± 3,8 cm (prosečna dužina ± SD), dok se raspon težina kretao od 150 do 1945 g, sa prosečnom vrednošću od 397,84 ± 171,85 g. Analiza dužinsko-težinskog odnosa kod obe vrste pokazala je da se vrednost parametra b razlikuje od idealne izometrijske vrednosti 3. Kod orade vrednost parametra b iznosi 2,4851, dok je kod brancina vrednost parametra b iznosi 3,0591. Studentov t-test pokazao je da se parametar b dužinsko-težinskog odnosa kod ukupnog uzorka orade i brancina nije statistički značajno razlikovao od idealne izometrijske vrednosti 3. Koeficijent kondicije kod obe vrste određen je pomoću Le Cren-ove i Fulton-ove formule po mesecima istraživanja i prema dužinskim klasama. Prosečan koeficijent kondicije orade (Slika 3.) iznosi Ka=0,9467± 0,099 (Le Cren, 1951), odnosno Ka=1,4607 ± 0,1875 (Fulton, 1904), a od istraživanih meseci najniža vrednost zabeležena je u februaru, Ka=0,947 (Le Cren), odnosno Ka=1,4196 (Fulton). Kod brancina prosečan koeficijent kondicije (Slika 4.) za ceo ispitivani uzorak iznosi Ka=1,0164±0,0627 (Le Cren), odnosno Ka=1,0041±0,0721 (Fulton), a od istraživanih meseci najniža vrednost zabeležena je u februaru mesecu Ka=0,9656 (Le Cren), odnosno Ka=0.9512 (Fulton)

Procjena populacije škampa - nephrops norvegicus (linnaeus, 1758) u Jadranskom moru alternativnim metodama

Škamp (Nephrops norvegicus) spada u gospodarski najvažnije vrste rakova na području Mediterana i severnoistočnog Atlantika kojeg se godišnje izlovi preko 60000 t. Rasprostranjen je u istočnom Atlantiku i diljem Mediterana od 20 do 800 m dubine. Obitava na muljevitim sedimentima u kojem iskopava karakteristične tunele. Najveća gustoća populacije u Jadranskom moru zabeležena je na području Jabučke kotline, Velebitskom kanalu, Kvarneru i Kvarneriću. U južnom delu Jadrana gustoća populacije je osetno manja. Škamp se u Jadranskom moru intenzivno izlovljava uglavnom povlačnom pridnenom mrežom koćom od strane mnogobrojne ribarske flote svih jadranskih zemalja. Usled toga došlo je do negatvinih promena ukupne biomase, te demografske strukture populacije škampa. Da bi se uspostavilo odgovorno i održivo ribarstvo, te zaštitila populacija škampa provode se brojna istraživanja i monitorinzi, te procene stanja populacije. Ova istraživanja uglavnom se temelje na ribarstveno biološkim metodama kao što su praćenje totalnog ulova, kretanje CPUE ili analitčkih metoda (VPA, LCA and yield-per-recruit analysis). Glavni nedostatak ovih metoda je što se temelje na pretpostavci reprezentativnog uzorkovanja populacija što kod škampa, zbog njegovih bioloških karakteristika, nije slučaj. Obzirom da škamp obitava u tunelima, koje iskopava u sedimentu, on može biti uzorkovan samo kada se nalazi izvan njih, a izlazak varira ovisno o sezoni, dobu dana, veličini, spolu te stadiju zrelosti. Da bi se postiglo reprezentativno uzorkovanje u svrhu dobivanja tačne procene stanja populacije u poslednje vreme sve više se koristi alternativna metoda istraživanja upotrebom povlačne podvodne kamere (UWTV). Ova metoda se zasniva na promatranju morfoloških karakteristika morskog dna da bi se identifikovale vrste koje obitavaju u tunelima na osnovu karkterističnog izgleda otvora tunela. Da bi se tačno idenetifikovala vrsta koja obitava u tunelima treba promatrati oblik, dijametar, razdaljinu, orijentaciju, grupiranje otvora, prisustvo vrste ili tragova te drugih značajnih parametra. Dobivene vrednosti se zajedno sa rezultatima ribarstveno bioloških istraživanja analitičkim metodama preračunavaju se u indeks biomase po površini. Metodologija istraživanja provodi se upotrebom specijalnih podvodnih kamera montiranih na sanje koje se istraživačkim brodom povlače po morskom dnu određenim vremenom i brzinom. Video snimka, zajedno s ostalim zabeleženim oceanografskim podacima, se putem optičkog kabla u realnom vremenu prenosi u kontrolnu jedinicu na brodu. Snimljeni materijal se analizira prema međunarodnom protokolu (ICES) da bi se omogućila ispravna usporedba podataka. UWTV metoda zajedno s drugim ribarstveno biološkim metodama značajno doprinosi sistematskom praćenju stanja i procjene populacije škampa, te uvođenju odgovornog i održivog iskorištavanja bioloških obnovljivih resursa zasnovanog na znanstvenim saznanjima