Arpp19 Promotes Myc and Cip2a Expression and Associates with Patient Relapse in Acute Myeloid Leukemia

Disease relapse from standard chemotherapy in acute myeloid leukemia (AML) is poorly understood. The importance of protein phosphatase 2A (PP2A) as an AML tumor suppressor is emerging. Therefore, here, we examined the potential role of endogenous PP2A inhibitor proteins as biomarkers predicting AML relapse in a standard patient population by using three independent patient materials: cohort1 (n = 80), cohort2 (n = 48) and The Cancer Genome Atlas Acute Myeloid Leukemia (TCGA LAML) dataset (n = 160). Out of the examined PP2A inhibitors (CIP2A, SET, PME1, ARPP19 and TIPRL), expression of ARPP19 mRNA was found to be independent of the current AML risk classification. Functionally, ARPP19 promoted AML cell viability and expression of oncoproteins MYC, CDK1, and CIP2A. Clinically, ARPP19 mRNA expression was significantly lower at diagnosis (p = 0.035) in patients whose disease did not relapse after standard chemotherapy. ARPP19 was an independent predictor for relapse both in univariable (p = 0.007) and in multivariable analyses (p = 0.0001) and gave additive information to EVI1 expression and risk group status (additive effect, p = 0.005). Low ARPP19 expression was also associated with better patient outcome in the TCGA LAML cohort (p = 0.019). In addition, in matched patient samples from diagnosis, remission and relapse phases, ARPP19 expression was associated with disease activity (p = 0.034), indicating its potential usefulness as a minimal residual disease (MRD) marker. Together, these data demonstrate the oncogenic function of ARPP19 in AML and its risk group independent role in predicting AML patient relapse tendency

Phosphoproteome and drug-response effects mediated by the three protein phosphatase 2A inhibitor proteins CIP2A, SET, and PME-1

Protein phosphatase 2A (PP2A) critically regulates cell signaling and is a human tumor suppressor. PP2A complexes are modulated by proteins such as cancerous inhibitor of protein phosphatase 2A (CIP2A), protein phosphatase methylesterase 1 (PME-1), and SET nuclear proto-oncogene (SET) that often are deregulated in cancers. However, how they impact cellular phosphorylation and how redundant they are in cellular regulation is poorly understood. Here, we conducted a systematic phosphoproteomics screen for phosphotargets modulated by siRNA-mediated depletion of CIP2A, PME-1, and SET (to reactivate PP2A) or the scaffolding A-subunit of PP2A (PPP2R1A) (to inhibit PP2A) in HeLa cells. We identified PP2A-modulated targets in diverse cellular pathways, including kinase signaling, cytoskeleton, RNA splicing, DNA repair, and nuclear lamina. The results indicate nonredundancy among CIP2A, PME-1, and SET in phosphotarget regulation. Notably, PP2A inhibition or reactivation affected largely distinct phosphopeptides, introducing a concept of nonoverlapping phosphatase inhibition- and activation-responsive sites (PIRS and PARS, respectively). This phenomenon is explained by the PPP2R1A inhibition impacting primarily dephosphorylated threonines, whereas PP2A reactivation results in dephosphorylation of clustered and acidophilic sites. Using comprehensive drug-sensitivity screening in PP2A-modulated cells to evaluate the functional impact of PP2A across diverse cellular pathways targeted by these drugs, we found that consistent with global phosphoproteome effects, PP2A modulations broadly affect responses to more than 200 drugs inhibiting a broad spectrum of cancer-relevant targets. These findings advance our understanding of the phosphoproteins, pharmacological responses, and cellular processes regulated by PP2A modulation and may enable the development of combination therapies

Common Inflammation-Related Candidate Gene Variants and Acute Kidney Injury in 2647 Critically Ill Finnish Patients

Acute kidney injury (AKI) is a syndrome with high incidence among the critically ill. Because the clinical variables and currently used biomarkers have failed to predict the individual susceptibility to AKI, candidate gene variants for the trait have been studied. Studies about genetic predisposition to AKI have been mainly underpowered and of moderate quality. We report the association study of 27 genetic variants in a cohort of Finnish critically ill patients, focusing on the replication of associations detected with variants in genes related to inflammation, cell survival, or circulation. In this prospective, observational Finnish Acute Kidney Injury (FINNAKI) study, 2647 patients without chronic kidney disease were genotyped. We defined AKI according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria. We compared severe AKI (Stages 2 and 3, n = 625) to controls (Stage 0, n = 1582). For genotyping we used iPLEX(TM) Assay (Agena Bioscience). We performed the association analyses with PLINK software, using an additive genetic model in logistic regression. Despite the numerous, although contradictory, studies about association between polymorphisms rs1800629 in TNFA and rs1800896 in IL10 and AKI, we found no association (odds ratios 1.06 (95% CI 0.89-1.28, p = 0.51) and 0.92 (95% CI 0.80-1.05, p = 0.20), respectively). Adjusting for confounders did not change the results. To conclude, we could not confirm the associations reported in previous studies in a cohort of critically ill patients.Peer reviewe

Fluid challenges in intensive care: the FENICE study A global inception cohort study

Fluid challenges (FCs) are one of the most commonly used therapies in critically ill patients and represent the cornerstone of hemodynamic management in intensive care units. There are clear benefits and harms from fluid therapy. Limited data on the indication, type, amount and rate of an FC in critically ill patients exist in the literature. The primary aim was to evaluate how physicians conduct FCs in terms of type, volume, and rate of given fluid; the secondary aim was to evaluate variables used to trigger an FC and to compare the proportion of patients receiving further fluid administration based on the response to the FC.This was an observational study conducted in ICUs around the world. Each participating unit entered a maximum of 20 patients with one FC.2213 patients were enrolled and analyzed in the study. The median [interquartile range] amount of fluid given during an FC was 500 ml (500-1000). The median time was 24 min (40-60 min), and the median rate of FC was 1000 [500-1333] ml/h. The main indication for FC was hypotension in 1211 (59 %, CI 57-61 %). In 43 % (CI 41-45 %) of the cases no hemodynamic variable was used. Static markers of preload were used in 785 of 2213 cases (36 %, CI 34-37 %). Dynamic indices of preload responsiveness were used in 483 of 2213 cases (22 %, CI 20-24 %). No safety variable for the FC was used in 72 % (CI 70-74 %) of the cases. There was no statistically significant difference in the proportion of patients who received further fluids after the FC between those with a positive, with an uncertain or with a negatively judged response.The current practice and evaluation of FC in critically ill patients are highly variable. Prediction of fluid responsiveness is not used routinely, safety limits are rarely used, and information from previous failed FCs is not always taken into account

Common Inflammation-Related Candidate Gene Variants and Acute Kidney Injury in 2647 Critically Ill Finnish Patients

Acute kidney injury (AKI) is a syndrome with high incidence among the critically ill. Because the clinical variables and currently used biomarkers have failed to predict the individual susceptibility to AKI, candidate gene variants for the trait have been studied. Studies about genetic predisposition to AKI have been mainly underpowered and of moderate quality. We report the association study of 27 genetic variants in a cohort of Finnish critically ill patients, focusing on the replication of associations detected with variants in genes related to inflammation, cell survival, or circulation. In this prospective, observational Finnish Acute Kidney Injury (FINNAKI) study, 2647 patients without chronic kidney disease were genotyped. We defined AKI according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria. We compared severe AKI (Stages 2 and 3, n = 625) to controls (Stage 0, n = 1582). For genotyping we used iPLEX(TM) Assay (Agena Bioscience). We performed the association analyses with PLINK software, using an additive genetic model in logistic regression. Despite the numerous, although contradictory, studies about association between polymorphisms rs1800629 in TNFA and rs1800896 in IL10 and AKI, we found no association (odds ratios 1.06 (95% CI 0.89-1.28, p = 0.51) and 0.92 (95% CI 0.80-1.05, p = 0.20), respectively). Adjusting for confounders did not change the results. To conclude, we could not confirm the associations reported in previous studies in a cohort of critically ill patients

Heme oxygenase-1 repeat polymorphism in septic acute kidney injury

Acute kidney injury (AKI) is a syndrome that frequently affects the critically ill. Recently, an increased number of dinucleotide repeats in the HMOX1 gene were reported to associate with development of AKI in cardiac surgery. We aimed to test the replicability of this finding in a Finnish cohort of critically ill septic patients. This multicenter study was part of the national FINNAKI study. We genotyped 300 patients with severe AKI (KDIGO 2 or 3) and 353 controls without AKI (KDIGO 0) for the guanine-thymine (GTn) repeat in the promoter region of the HMOX1 gene. The allele calling was based on the number of repeats, the cut off being 27 repeats in the S-L (short to long) classification, and 27 and 34 repeats for the S-M-L2 (short to medium to very long) classification. The plasma concentrations of heme oxygenase-1 (HO-1) enzyme were measured on admission. The allele distribution in our patients was similar to that published previously, with peaks at 23 and 30 repeats. The S-allele increases AKI risk. An adjusted OR was 1.30 for each S-allele in an additive genetic model (95% CI 1.01-1.66; p = 0.041). Alleles with a repeat number greater than 34 were significantly associated with lower HO-1 concentration (p<0.001). In septic patients, we report an association between a short repeat in HMOX1 and AKI risk

New, biobased carbon foams

Abstract The use of biomass has grown tremendously among energy-producing factories recently. In addition to burning biomass to produce heat and electricity, new and environment friendly products are being developed in order to utilize biomass more efficiently. Due to the variety of rich carbon sources in biomass, this thesis focuses on the use of such carbon sources in producing activated carbon foams. The first part of this thesis consists of two sections. First, it notes that carbon foams are produced using sugar as a source of carbon. It further notes that the sugar-based carbon foams that have been produced were too brittle and, therefore, require further adjustment in order to produce mechanically stronger foams. In the second section of the first part, this thesis addresses how hydrolysable tannin, as well as hydrolysable tannin in combination with different lignin types, is used to produce carbon foams and activated carbon foams. This section also studies the physical properties of these foams. The results indicate that changing the catalyst during foaming, or using the right lignin-to-tannin ratio (25 w%) and a four-hour thermal treatment at 1073 K, obtains the highest influence on these foams’ mechanical strength. Up to 10 times stronger foams, can be achieved with this method. The second part of this thesis focuses on studying the properties and performance of activated carbon foams based on hydrolysable tannin, pine bark, and spruce bark extracts as catalyst supports in the conversion of furfural to 2-methylfuran and as adsorbents for the removal of methylene blue. Based on the results, chemically activated carbon foams from spruce bark work better than physically activated carbon foams in removing methylene blue from solutions due to their more developed pore size distribution and higher specific surface area. The performance of activated carbon foam derived from pine bark extracts in the conversion of furfural to 2-methylfuran was similar to commercial reference materials’ 58%.Tiivistelmä Biomassan hyödyntäminen energiaa tuottavissa laitoksissa on kasvanut hurjasti viime aikoina. Vaikka biomassaa poltetaankin lämmön ja energian tuotannon takia, uusia ja ympäristöystävällisiä tuotteita pyritään kuitenkin tuottamaan biomassasta, jotta sen hyödyntäminen olisi mahdollisimman tehokasta. Tässä opinnäytetyössä käytetään biomassan sisältäviä hiilirikkaita yhdisteitä kuten tanniineja, sokereita ja ligniiniä aktivoitujen hiilivaahtojen valmistamiseen. Väitöstutkimuksen ensimmäinen osa koostuu kahdesta osasta: Ensiksi, hiilivaahtoja ja aktiivihiilivaahtoja tuotetaan käyttämällä sokeria hiilen lähteenä. Tutkimuksissa huomattiin, että hiilivaahdot olivat mekaanisesti liian hauraita. Vahvempien vaahtojen tuottamiseksi, käytetään tutkimuksen toisessa osassa hydrolysoituvaa tanniinia ja hydrolysoituvaa tanniinia yhdessä eri ligniinityyppien kanssa hiilivaahtojen ja aktiivihiilivaahtojen tuottamiseksi sekä tutkittiin niiden fysikaalisia ominaisuuksia. Tulokset osoittivat, että mekaaniseen lujuuteen voidaan vaikuttaa käyttämällä eri katalyyttiä vaahdotuksessa tai käyttämällä oikeaa ligniini / tanniinisuhdetta (25 paino-%) ja 4 tunnin lämpökäsittelyä lämpötilassa 1073 K. Jopa 10 kertaa vahvempia vaahtoja voidaan saavuttaa tällä tavoin. Väitöstutkimuksen toisessa osassa tutkitaan puhtaista hydrolysoituvista tanniini-, mänty- ja kuusenkuoriuutteista valmistettuja aktiivihiilivaahtoja furfuraalin konversiossa 2-metyylifuraaniksi ja adsorbentteina metyleenisinisen poistossa. Tulosten perusteella kuusen kuoriuutteesta tehdyt kemiallisesti aktivoidut hiilivaahdot toimivat metyleenisinisen poistossa kehittyneemmän huokoskokojakaumansa ja suuremman ominaispinta-alansa vuoksi paremmin kuin fysikaalisesti aktivoidut hiilivaahdot. Männyn kuoriuutteesta valmistettu aktiivihiilivaahto toimi furfuraalin konversiossa 2-metyylifuraaniksi lähes kaupallisten vertailukatalyyttien 58 %:n tavoin

Catalytic effect of transition metals (copper, iron, and nickel) on the foaming and properties of sugar-based carbon foams

Abstract Recently, bio-based carbon foams have gained much interest in many chemical industry fields because of their unique structure and properties. This study provides new information on the effects of catalytic metals (iron, nickel, and copper) on the foaming process. Specifically, the effects of these catalysts on the density, foam growth, and cell size and then further on the pore size distribution and specific surface areas after the physical activation are considered. Furthermore, some of the activated sugar foams were used in adsorption tests using methylene blue as adsorbent. Results showed that the highest effect on foam density was obtained using the iron catalyst in the foaming process. In addition, increasing the iron amount, the development of micro-pores decreased from 95.2 to 60.3% after cabonization and activation of the foams. Nickel and iron had the highest and lowest effect on foam rise at 1375 and 500%, respectively. Interestingly, when the nickel catalyst was used, cell sizes and surface areas two times larger than those when the foams were prepared with the iron and copper catalysts was obtained. The specific surface area of activated sugar-based carbon foams changed significantly with the increased copper amount inside the foaming solution in compared with iron or nickel catalyst. Methylene blue adsorption capacity of additional series of activated sugar foams decreased from 28 to 9% when meso-pore amount decreased

Physical activation and characterization of tannin-based foams enforced with boric acid and zinc chloride

Abstract In this study, tannin-furanic-based foams enforced with H3BO3 and ZnCl2 are investigated, as well as their properties such as mechanical strength, specific surface area, and pore size distribution. From an industrial point of view, the aforementioned properties of these foams play a key role when used as catalyst, adsorbent, or gas storing materials. Therefore, this study aims to prove that such enforced tannin-furanic foams are promising materials for these types of applications. According to the results, materials that are up to five times stronger can be achieved by carbonizing the foams in comparison to maturing them. With physical activation, it was possible to obtain a specific surface area as high as 845 m2/g with a pore volume of up to 0.35 cm3/g. Chemical activation, using ZnCl2as the activating agent, produced a specific surface area and pore volume of 737 m2/g and 0.31 cm3/g. However,the pore sizes were mostly microporous, independently of activation procedure used

Activated carbon from hydrolysis lignin:effect of activation method on carbon properties

Abstract This study presents the effects of different activation methods to produce activated carbon from the hydrolysis lignin. Pretreatment of the feedstock with common mineral acids (HCL, HNO₃, and H₃PO₄), different steam rates for physical activation, and different chemical activating agents (ZnCl₂, Na₂CO₃, and KOH) for chemical activation were investigated. The pretreated biomass was carbonized and activated in one-stage process and the surface characteristics, such as total pore volume, pore size distribution and specific surface area, were investigated. The results showed that the activated carbon surface properties were not greatly affected by acid pretreatment. Brunauer-Emmett-Teller (BET) surface areas as high as 616 m²/g could be achieved with physical activation and 2054 m²/g with chemical activation. Different steam rates in the selected interval (0.5–2 cm³/min) did not change the pore size distribution but had small positive effect on the specific surface area, while chemical activation with ZnCl₂ increased the mesoporosity, and activation with KOH increased the microporosity and oxygen groups in the form of ether and alcohol bonds