Towards targeting SAMHD1 to improve cytarabine therapy for hematological malignancies

Acute myeloid leukemia (AML) is a hematological cancer where myeloid stem cells are transformed into malignant cells, filling and replacing the cells in a healthy bone marrow. Cytarabine is a nucleoside analog used in chemotherapy for hematological malignancies, such as AML, where it is combined with an anthracycline as a standard treatment. Nevertheless, this nucleoside analog in itself is not an active cytotoxic compound. Cytarabine is a prodrug that needs metabolism to become its active triphosphate form, which disturbs DNA synthesis and therefore is effective against rapidly dividing cancer cells. However, despite treatment, this leukemia might relapse, when treatment responses are usually less effective. SAMHD1 (SAM and HD domain containing protein 1) has enzymatic activity that could explain why cytarabine treatment is not effective in some patient populations. SAMHD1 displays enzymatic activity against the active cytarabine metabolite, converting this active triphosphate (Ara-CTP) back to its inactive form (Ara-C), similarly to deoxynucleoside triphosphates (dNTPs) that are converted to their corresponding nucleoside core along with inorganic triphosphates. Recent studies indicate that inhibition of SAMHD1 could potentiate the efficacy of cytarabine treatment. SAMHD1 protein abundance has connections to ara-C response in leukemia cells: ara-C cytotoxicity is enhanced in THP-1 SAMHD1 knock out (KO) cells in comparison to proficient cell line variant (THP-1 ctrl). In this thesis work, I optimized a cell-based drug-combination assay and used it to test and evaluate combination treatment of ara-C and candidate SAMHD1 inhibitor compounds in a panel of hematological cancer cell lines and indeed demonstrated that creating a SAMHD1 deficient phenotype with chemical compounds can potentiate cytarabine-induced cytotoxicity in SAMHD1 dependent manner. Keywords: Acute myeloid leukemia (AML), cytarabine (Ara-C), SAMHD1, synergy, combination treatment, precision medicin

LÄMPÖLAITOKSEN KORJAUS : Heinäveden Aluelämpö Oy:n hakkeenkuljetusketjun korjaus- ja parannustyö

Opinnäytetyö suoritettiin osana Heinäveden Aluelämpö Oy:n Haketien laitoksen laitteiston peruskorjaus projektia. Projekti sai alkunsa tammikuussa 2016, jolloin Haketien laitoksen hakkeensiirtojärjestelmän alku-päässä käyttösylinteri irtosi alustastaan. Käyttösylintereitä oli jo aiemmin koetettu tukea eri menetelmin mutta tarkoitus oli suunnitella kestävä kiinnitys sylinterille. Myöhemmin toukokuussa alkoi koko hakesiilon remontointi ja uutena ratkaisuna etsittiin konehuoneen ja hakesiilon väliin tankopurkaimien läpivienteihin tiivistys joka kestää eikä vuoda puuhaketta konehuoneeseen. Uudemman Arimax- kattilan hakkeensyöttökoneistossa oli ongelmia. Kahdella hydraulisylinterillä toimiva järjestelmä jumiutui aika-ajoin syöttölevyn mennessä vinoon. Liikeradan suorassa pysymiselle haettiin toi-miva ratkaisu. Vanhemman Ekopoint- kattilan tuhkatilan helmat olivat ruostuneet eikä paikkaaminen enää ollut järkevää. Työ suoritettiin käyden paikan päällä tutustuen ongelmiin. Muutoin työ oli suunnittelua, jossa työkaluna käytettiin Solidworks- ohjelmaa. Työssä sovellettiin paljon lujuusopin teoriaa. Työssä sovellettiin myös FEM- laskentaa. Työssä pyrittiin yksinkertaisiin ja helposti valmistettaviin ratkaisuihin. Lisäksi valmiita standardio-sia pyrittiin käyttämään niin paljon kuin mahdollista. Silti rakenteista tuli haastavia valmistusteknisesti. Kat-tilan helman korjausprosessissa päädyttiin materiaalin vaihtoon vakiona käytetystä mustasta rakenneteräk-sestä AISI 316L teräkseen. Tämä asetti hitsausmetallurgisesti uuden kysymyksen eripariliitoksen suhteen. Koska kyseessä on tärkeä infrastruktuuria palveleva kokonaisuus, suunnittelussa paneuduttiin enemmän varmoihin ratkaisuihin kuin materiaalin säästöön tai rakenteiden keveyden optimointiin. Todettiin että lai-toksen suunnitellut yritys ei ollut perehtynyt lujuusteknillisiin näkökohtiin koska vastaavanlaisiin suurten voimien laitteistoihin tehdään vankka teräsrunko eikä asenneta käyttölaitteita betoniraudoitukseen, koska betoniraudoituksella on tarkoituksena vahvistaa valua itseään eikä kantaa ylimääräisiä voimia. Nyt tanko-purkaimien käyttösylintereiden kiinnityksien kesto on karkeastikin arvioiden 65 – 70 vuotta joka kattaa mo-ninkertaisesti laitoksen suunnitellun loppuelinkaaren.Abstract The aim of this final project was to do part of the renovation of equipment. The work was commissioned by Heinäveden aluelämpö Oy and it was done in the Haketie plant. Earlier a machine had got loose of the base and therefore the aim was to plan a long lasting and strong engine suspension. The work was done exploring the problems on the spot. SolidWorks program was used as a design tool. A lot of theory of strength calculation was applied as well as FEM calculation. The aim was to find easily im-plementable solutions. In addition, existing standard parts were used as much as possible. Still, the manu-facturing technique of the structures turned out challenging. In the boiler heal repair process it was decided to replace the standard material with the structural steel AISI 316L which lead to another problem with me-tal. Since the design was focused on secure solutions more than saving material or optimizing structural light-ness. It was found out that the company that had designed the plant was not familiar with the strength-tech-nical aspects since similar heavy-duty installations are made with a solid steel frame and no concrete-rein-forcing actuators are installed since the concrete reinforcement is intended to reinforce casting and not to carry extra loads. Now, the life span of the cylinder drive cylinders is roughly estimated between 65 and 70 years, exceeding the life- cycle planned for the plant

Methods for Analyzing the Structure of Creases in Heat Sealed Paperboard Packages

Press-forming of paperboard has been previously studied by several authors. A point of interest regarding gas tight heat sealing of the packages are the creases in the package. The objective of this article was to study and compare different microscopic imaging methods to research an optimal imaging method for the formation of creases in the press-forming process of polymer coated paperboard trays. The studied methods were: Scanning electrode microscopy (SEM), X-ray Microtomography, Optical light microscopy and Polarized light microscopy. All four tested methods delivered clear images. Casting of the samples in an acrylic resin and light microscope imaging was found to be the most suitable method for the analysis of heat sealed creases and leakage detection

Plant residue mulch increases measured and modelled soil moisture content in the effective root zone of maize in semi-arid Kenya

Difficulties in efficient utilization of seasonal precipitation cause limitations in yields and even total crop failure on rainfed farms in semi-arid East Africa. The objective of the present study was to find out if covering the soil with plant residue mulch at a semi-arid site could retain water in the soil between precipitation events and build dry spell resilience by reducing soil water evaporation and increasing infiltration to deeper soil. Covering soil with plant residue mulch was studied at a smallholder farm in semi-arid Kenya by continuously measuring volumetric soil moisture content with soil sensors at multiple depths in bare soil and in maize (Zea mays L.) plant residue mulched soil. A physically based one-dimensional soil moisture model was calibrated and used to estimate the effect of plant residue mulch on soil moisture over a two-year period (multiple growing seasons). The modelled multiyear time series provides an estimate of the effect residue mulches of different thicknesses have on soil moisture over time. The simple soil moisture model was able to estimate soil moisture in the effective root zone of maize. By comparing measured data from mulched and uncovered soil and by model prediction, it was demonstrated that maize residue mulch conserved soil moisture over time in the effective root zone of maize compared to bare soil. During the two-year period mulching increased the total amount of days when measured relative soil moisture (s) exceeded water stress limit of maize (s*) by 24%-46%. Moisture accumulated in the mulched profile, especially in the deeper layers of the effective root zone. Calculations indicated that further increasing mulch thickness (delta(m)) from 1 to 3 cm would have increased the total days when s > s* 59%. Furthermore, increasing delta(m) from 3 to 5 cm would have resulted in 25% increase in total days when s > s*. According to our calculations mulching (delta(m) > 1 cm) could have maintained s > s* throughout a 19 days dry spell that occurred during the measurement period. The demonstrated moisture conserving effect of mulch increases with delta(m), but availability of plant residue may set limits on mulch application rates. The results suggest that maize residue mulching is as an accessible and feasible method for conserving soil moisture in the effective root zone in dryland smallholder systems in East Africa.Peer reviewe