The biochemical relapse of prostate cancer was determined if there were two consecutive

rises of prostate-specific antigen (PSA) level above 0.2 ng/mL or according to the attending physician’s opinion, there was a need for adjuvant treatment even with selleck kinase inhibitor onetime rise of PSA level above 0.2 ng/mL.\n\nResults. There was no significant difference between the HGPIN and non-HGPIN groups in terms of time to biochemical relapse and frequency of biochemical relapses, time before surgery, the timing of the HGPIN diagnosis, age, or PSA level. After radical prostatectomy, patients in the HGPIN group were found to have significantly more often poorer cancer cell differentiation according to the Gleason score (>= 7 vs. <7; P=0.001) buy LDN-193189 and higher TNM stage (T3a,b vs. T2a,b,c; P=0.001). Fewer positive resection

margins were diagnosed in the HGPIN group (P=0.05). The groups did not differ in terms of the degree of differentiation according to the Gleason score or perineural invasion (P=0.811 and P=0.282, respectively).\n\nConclusions. HGPIN was more often associated with the characteristics of the poor prognosis for relapse of prostate cancer: poorer tumor cell differentiation according to the Gleason score and more cases of higher TNM stage. HGPIN did not have any influence on biochemical relapse of the disease during the short-term follow-up.”
“Association mapping is a powerful approach for exploring the molecular basis of phenotypic variations in plants. A peanut (Arachis hypogaea L.) mini-core

collection in China comprising 298 accessions was genotyped using 109 simple sequence repeat selleck (SSR) markers, which identified 554 SSR alleles and phenotyped for 15 agronomic traits in three different environments, exhibiting abundant genetic and phenotypic diversity within the panel. A model-based structure analysis assigned all accessions to three groups. Most of the accessions had the relative kinship of less than 0.05, indicating that there were no or weak relationships between accessions of the mini-core collection. For 15 agronomic traits in the peanut panel, generally the Q+K model exhibited the best performance to eliminate the false associated positives compared to the Q model and the general linear model-simple model. In total, 89 SSR alleles were identified to be associated with 15 agronomic traits of three environments by the Q+K model-based association analysis. Of these, eight alleles were repeatedly detected in two or three environments, and 15 alleles were commonly detected to be associated with multiple agronomic traits. Simple sequence repeat allelic effects confirmed significant differences between different genotypes of these repeatedly detected markers. Our results demonstrate the great potential of integrating the association analysis and marker-assisted breeding by utilizing the peanut mini-core collection.

The maximum rate of Cr(VI) removal was attained at a temperature of 37 degrees C, pH of 7.0-9.0, and biomass of 20 g/L when the initial Cr(VI) concentration was less than 50 mg/L. Under the optimum conditions, the Cr(VI) in tannery wastewater was treated with each cellular component of B. cereus

to detect its ability to reduce Cr(VI). The results showed that the removal rate of Cr(VI) for the cell-free extracts could reach 92.70%, which was close to that of the whole cells (96.85%), indicating that the Cr(VI) reductase generated by B. cereus is primarily intracellular. Additionally, during continuous culture of the B. cereus, the strain showed good consecutive growth and removal ability. After treatment of 20 mg/L Cr(VI) for 48 h, the B. cereus was observed by SEM and TEM-EDX. SEM images showed selleck that the B. cereus used to treat Cr(VI) grew

well and had a uniform cellular size. TEM-EDX analysis revealed large quantities of chromium in the B. cereus cells used to treat Cr(VI). Overall, the results presented herein demonstrate that B. cereus can be used as a new biomaterial to remove Cr(VI) from tannery wastewater.”
“Liver diseases are amongst the most serious health problems in the world today and hepatocellular carcinoma is one of the world’s deadliest cancers. The aim of the current study was to evaluate the protective effect of sider EPZ5676 concentration honey and/or Korean ginseng extract (KGE) against carbon tetrachloride (CCl4)-induced hepato-nephrotoxicity in rat. Eighty male Sprague-Dawley (SD) rats were allocated into different groups and over a 4-week period, they orally received honey and/or KGE or were treated either with CCl4 alone (100 mg/kg b.w) or with CCl4 after a pretreatment period with honey, KGE or a combination of both. Clinical, clinico-pathological and histopathological evaluations were done and CCl4-treated groups were compared with rats receiving no treatment and with rats given honey, KGE

or A-1210477 solubility dmso a combination of these substances. The results indicated that oral administration of CCl4 induced severe hepatic and kidney injury associated with oxidative stress. The combined treatment with CCl4 plus honey and/or KGE resulted in a significant improvement in all evaluated parameters. This improvement was prominent in the group receiving CCl4 after combined pretreatment with honey and KGE. Animals receiving honey and/or KGE (without CCl4-treatment) were comparable to the control untreated group. It could be concluded that honey and KGE protect SD rats against the severe CCl4-induced hepatic and renal toxic effects. Our results suggest that the protective activity of honey and KGE may have been related to their antioxidant properties. (C) 2011 Elsevier GmbH. All rights reserved.”
“Calcium channel blockers can modulate the nociceptive threshold. However, the underlying mechanism(s).

These studies indicate that FGF-23 inhibits phosphate transport in the mouse kidney by processes that involve the scaffold protein NHERF-1. In addition, FGF-23 synergizes with PTH to inhibit phosphate transport by facilitating the activation of the PTH signal transduction pathway.”
“Lipid rafts represent a sub-compartment of the plasma membrane that co-ordinate and regulate varieties Combretastatin A4 of signalling processes, whereas caveolins are the integral membrane protein of the lipid raft. Recent evidence demonstrated the pivotal role of caveolins in cardioprotection against ischaemic injury, although their mechanism

of action is not clear. However, new understanding of epigenetic modification www.selleckchem.com/screening/gpcr-library.html during ischaemia reperfusion suggests additional targeted approaches that have not been explored before. To study the role of caveolin on epigenetic regulation, isolated mouse heart was prepared from wild-type (WT) and caveolin-1 knockout (Cav-1 KO) mouse and preconditioned them with four cyclic episodes of ischaemia/reperfusion followed by 30 min. global

ischaemia and 120 min. reperfusion. We found that Cav-1 KO mouse abolished the acetylation of histone (H3 and H4) and increased the methylation of histone in the preconditioned heart. The increased histone methylation was significantly correlated with an increased level of histone methyltranferase G9a protein and increased the level of histone decaetylase (HDAC) activity. Cav-1 KO mouse also decreased the translocation of forkhead transcription factor (FOXO3a) to the nucleus and reduced the induction of the expression of SIRT-1 in the preconditioned heart. Cardioprotective property of Cav-1 was further confirmed by reduced ventricular function, increased cardiomyocyte apoptosis, increased expression of junas kinase (JNK) and Bax and decreased CYT387 solubility dmso expression of phospho-adenosine monophosphate-activated protein kinase (AMPK), phospho-AKT and B cell

lymphoma-2 (Bcl-2) in Cav-1 KO preconditioned heart. The results clearly indicate that Cav-1 induces cardioprotection through epigenetic regulation.”
“This review provides an update of ongoing efforts to expand our understanding of the diversity inherent within the Schistosomatidae, the parasites responsible for causing schistosomiasis and cercarial dermatitis. By revealing more of the species present, particularly among understudied avian schistosomes, we gain increased understanding of patterns of schistosome diversification, and their abilities to colonize new hosts and habitats. Schistosomes reveal a surprising ability to switch into new snail and vertebrate host species, into new intrahost habitats, and may adopt novel body forms in the process. Often these changes are not associated with deep splits or long branches in their phylogeny, suggesting some are of relatively recent origin.

Poly (ethylene glycol) functionalized with methacrylate at one end was reacted with 2-bromopropionyl chloride to form a macromonomeric initiator for

ATRP. ATRP was found to be a more controllable polymerization method than conventional free radical polymerization in view of fewer cross-linked polymers and highly branched polymers produced from macromonomer initiators as well. In another scenario, ATRP of N-isopropylacrylamide (NIPAM) was initiated by MIM-ATRP SEN0014196 to obtain PEG-b-PNIPAM branched block/graft copolymers. Thermal analysis, FTIR, H-1 NMR, TEM, and SEM techniques were used in the characterization of the products. They had a thermo-responsive character and exhibited volume phase transition at similar to 36 degrees C. A plasticizer effect of PEG in graft copolymers was

also observed, indicating a lower glass transition temperature than that of pure PNIPAM. Homo and copolymerization kinetics were also evaluated. (C) 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012″
“Many insignificant events in our daily life are forgotten quickly but can be remembered for longer when other memory-modulating events occur before or after them. This phenomenon has been investigated in animal models in a protocol in which weak memories persist longer if exploration in a novel context is introduced around the time of memory encoding.

This study aims to understand whether other types of rewarding or novel tasks, such MEK phosphorylation as rewarded learning in a T-maze and novel object recognition, can also be effective memory-modulating events. Rats were trained in a delayed matching-to-place Proteasome inhibitor task to encode and retrieve food locations in an event arena. Weak encoding with only one food pellet at the sample location induced memory encoding but forgetting over 24 h. When this same weak encoding was followed by a rewarded task in a T-maze, the memory persisted for 24 h. Moreover, the same persistence of memory over 24 h could be achieved by exploration in a novel box or by a rewarded T-maze task after a “non-rewarded” weak encoding. When the one-pellet weak encoding was followed by novel object exploration, the memory did not persist at 24 h. Together, the results confirm that place encoding is possible without explicit reward, and that rewarded learning in a separate task lacking novelty can be an effective memory-modulating event. The behavioral and neurobiological implications are discussed.”
“Chinese scorpion Buthus martensii Karsch (BmK) venom is a rich source of neurotoxins which bind to various ion channels with high affinity and specificity and thus widely used as compounds to modulate channel gating.

These image volumes typically contain a large number of articulated this website structures, which makes registration more difficult than the registration of head images, to which the majority of registration algorithms have been

applied. This article presents a new method for the automatic registration of whole body computed tomography (CT) volumes, which consists of two main steps. Skeletons are first brought into approximate correspondence with a robust point-based method. Transformations so obtained are refined with an intensity-based nonrigid registration algorithm that includes spatial adaptation of the transformation’s stiffness. The approach has been applied to whole body CT images of mice, to CT images of the human upper torso, and to human head and neck CT images. To validate the authors method on soft tissue structures, which are difficult to see in CT images, the authors use coregistered magnetic resonance images. They demonstrate that the approach they propose can successfully register image volumes even when these volumes are very different in size and shape or if they have been acquired with the subjects in different positions. (c) 2008 American Association of Physicists in Medicine.”
“Objectives: To evaluate the translation

of the IPSS (Hong Kong Chinese version 1) and to assess the applicability, validity, reliability and sensitivity of the instrument in both males and females with LUTS in Chinese

population.\n\nMethods: The translation of the IPSS (Hong Kong Chinese version 1) was reviewed through back translation. Modifications were made, resulting in the development learn more of The IPSS (Hong Kong Chinese version 2). The content validity was assessed by contend validity index. 233 subjects with LUTS were recruited in Hong Kong primary care settings for pilot psychometric testing. The construct validity was assessed by corrected item-total correlation and Pearson’s correlation test against ICIQ-UI SF, IIQ-7 and SF-12 v2. The reliability was assessed by the internal consistency (Cronbach’s Alpha coefficient) and test -retest reliability (Intraclass correlation coefficient). The Sensitivity was determined by performing known group comparisons by independent T-test.\n\nResults: The content validity CH5424802 in vitro index for all items could reach 1. Corrected item-total correlation scores were >= 0.4 for four symptom questions (feeling of incomplete bladder emptying, intermittency, weak stream and straining). Overall, the total symptom score moderately correlated with ICIQ-UI SF. The quality of life score moderately correlated with the IIQ-7 but weakly correlated with SF-12 v2. Overall, the reliability of the IPSS (Hong Kong Chinese version 2) was acceptable (Cronbach’s Alpha coefficient = 0.71, ICC of the symptom questions = 0.8, ICC of the quality of life question = 0.7).

Furthermore, treatment with curcumin could inhibit abnormal activated cyclin D1 protein level, and decrease the Brdu positive cells in

proportion to the A beta 25-35 treatment neurons.\n\nConclusions: All the results suggest that curcumin has a protective effect BMS-777607 ic50 against A beta-induced toxicity in cultured rat cortical neurons, the inhibition of cell cycle re-entry at least partly mediating the therapeutic effect of curcumin in the AD model in vitro.”
“Conventionally, a pulse taking platform is based on a single sensor, which initiates a feasible method of quantitative pulse diagnosis. The aim of this paper is to implement a pulse taking platform with a tactile array sensor. Three-dimensional wrist pulse signals are constructed, and the length, width, ascending slope, and descending slope are defined following the surface

of the wrist pulse. And the pressure waveform of the wrist pulse obtained through proposed pulse-taking platform has the same performance as the single sensor. Finally, the results of a paired samples t-test reveal that the repeatability of the proposal platform is consistent with clinical experience. On the other hand, the results of ANOVA indicate that differences exist among different pulse taking depths, and this NCT-501 research buy result is consistent with clinical experience in traditional Chinese medicine pulse diagnosis (TCMPD). Hence, the proposed pulse taking platform with an array sensor is feasible for quantification in TCMPD.”
“Coenzyme Q(10) (CoQ(10)) is an essential electron carrier in the mitochondrial respiratory chain and an important antioxidant. Deficiency

of CoQ(10) is a clinically and molecularly heterogeneous syndrome, which, to date, has been found to be autosomal recessive buy Semaxanib in inheritance and generally responsive to CoQ(10) supplementation. CoQ(10) deficiency has been associated with five major clinical phenotypes: (1) encephalomyopathy, (2) severe infantile multisystemic disease, (3) cerebellar ataxia, (4) isolated myopathy, and (5) nephrotic syndrome. In a few patients, pathogenic mutations have been identified in genes involved in the biosynthesis of CoQ(10) (primary CoQ(10) deficiencies) or in genes not directly related to CoQ(10) biosynthesis (secondary CoQ(10) deficiencies). Respiratory chain defects, ROS production, and apoptosis contribute to the pathogenesis of primary CoQ(10) deficiencies. In vitro and in vivo studies are necessary to further understand the pathogenesis of the disease and to develop more effective therapies. (C) 2010 Wiley-Liss, Inc. Dev Disabil Res Rev 2010;16:183-188.”
“Dynamic pulse buckling of woven E-Glass/Vinyl Ester and laminated E-Glass/Epoxy cylindrical shells subjected to uniform overpressure and asymmetric pressure pulse (side-on explosion) were examined. The solutions for the radial shell deformations were represented by Mathieu differential equations. The dynamic instability of the shells was determined from a Mathieu stability diagram.

Experimental data and molecular modeling support endostatin binding to the headpiece of the alpha v beta 3 integrin at the interface between the beta-propeller domain of the alpha v subunit and the beta A domain of the beta 3 subunit. In addition, we report that alpha 5 beta 1 and alpha v beta 3 integrins bind to heparin/heparan sulfate. The ectodomain of the alpha 5 beta 1 integrin binds to haparin with high affinity (K(D) = learn more 15.5 nM). The direct binding between integrins and heparin/heparan sulfate might explain why both heparan sulfate and alpha 5 beta 1 integrin are required for the localization

of endostatin in endothelial cell lipid rafts.”
“The Montreal Cognitive Assessment (MoCA) is a cognitive screening instrument created with the purpose of overcoming some of the insufficiencies of the Mini-Mental State Examination (MMSE). The MoCA evaluates more cognitive areas and is comprised of more complex tasks as compared with the MMSE, which makes it a more sensitive instrument

in the detection of Mild Cognitive Impairment (MCI), a state that often progresses to dementia. In this study we performed an analysis of the psychometric and diagnostic properties of the Portuguese experimental version of the MoCA in a clinical sample of 212 subjects with MCI and several dementia subtypes in a memory clinic setting. Additionally, we performed a see more Confirmatory Factor Analysis (CFA) to assess the MoCA’s latent factorial structure. In a clinical population, the MoCA is a valid and reliable instrument with good psychometric properties, revealing high sensitivity in identifying MCI and dementia patients who generally score within the normal range on the

MMSE. By using the parcels method, CFA results showed very good/excellent adjustment indexes. The practical implications of this CFA study allow us to propose a two factor model factorial structure for the MoCA: a first factor designated MEMORY, which includes memory, language and orientation subtests (the latter being closely correlated with the former), and a second factor designated ATTENTION/EXECUTIVE FUNCTIONS, comprised of attention, executive functions and visuospacial abilities tasks.”
“The aim of this study was to SB203580 molecular weight investigate the ratio of the transcription factors T-bet/GATA-3 in patients with allergic asthma. Forty-seven individuals with allergic asthma and 47 healthy control individuals provided 5 ml of anticoagulated peripheral venous blood. Lymphocytes in peripheral blood were isolated by Ficoll and treated with phytohemagglutinin (PHA) at a final concentration of 100 mg/l for 48 h. Interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) levels were detected using an enzyme-linked immunosorbent assay (ELISA), and the mRNA levels of both T-bet and GATA-3 were detected using reverse transcription polymerase chain reaction (RT-PCR).

(C)2013 AACR.”
“An imbalance between central glucocorticoid (GR) and mineralocorticoid (MR) receptors is proposed to underlie the HPA axis dysregulation that associates with susceptibility to psychopathology (anxiety, PTSD). To test selleck inhibitor this ‘balance hypothesis’ we examined whether the impact of MR levels upon HPA-axis control and behaviour depended on the relative levels of GR and vice versa. Avoiding antenatal maternal ‘programming’ effects by using littermates, we generated mice with forebrain MR over-expression

(MRhi) and/or simultaneous global GR underexpression (GR(lo)). We found a significant interaction between MR and GR in control of the HPA-axis under stressed but not basal conditions. With reduced GR levels, HPA-axis activity in response to restraint stress was enhanced, likely due to impaired negative feedback. However, high MR in concert with reduced GR minimised this HPA-axis overshoot in response to stress. MR:GR balance also played a role in determining strategies of spatial memory during a watermaze probe trial: when coupled with

GR under-expression, MRhi show enhanced perseveration, suggesting enhanced spatial recall or reduced exploratory flexibility. Other alterations in cognitive functions were specific to a single receptor without interaction, with both MRhi and GR(lo) manipulations independently impairing reversal learning in spatial and fear memory Selonsertib tasks. Thus, MR and GR interact in specific domains of neuroendocrine and cognitive control, but for other limbic-associated behaviours each receptor mediates its own repertoire of responses. Since modulation of HPA-axis and behavioural

dysfunction associated with high levels of MR, selective ligands or transcriptional regulators may afford novel therapeutic approaches to affective S63845 datasheet psychopathologles. (C) 2012 Elsevier Ltd. All rights reserved.”
“In this paper the utilization of the cyanobacteria Anabaena sp. in carbon dioxide removal processes is evaluated. For this, continuous cultures of this strain were performed at different dilution rates: alternatives for the recovery of the organic matter produced being also studied. A maximum CO2 fixation rate of 1.45 g CO2 L-1 day(-1) was measured experimentally, but it can be increased up to 3.0 g CO2 L-1 day(-1) outdoors. The CO2 is mainly transformed into exopolysaccharides, biomass representing one third of the total organic matter produced. Organic matter can be recovered by sedimentation with efficiencies higher than 90%, the velocity of sedimentation being 2 . 10(-4) s(-1). The major compounds were carbohydrates and proteins with productivities of 0.70 and 0.12 g L-1 day(-1), respectively. The behaviour of the cultures of Anabaena sp. has been modelized, also the characteristics parameters requested to design separation units being reported. Finally, to valorizate the organic matter as biofertilizers and biofuels is proposed. (C) 2009 Published by Elsevier Ltd.

In this study, the recent advances in the therapeutics of cerebral venous thrombosis with brief overview of epidemiology, clinical features, and imaging modalities were reviewed. With emerging imaging modalities and therapeutic options,

there has been a progress in ease of ability to diagnose and treat cerebral Immunology & Inflammation inhibitor venous thrombosis, but because of the lack of a much-needed randomized controlled trial, there is deficiency of a standardized algorithm/protocol for treatment of cerebral sinus thrombosis, which remains mostly at the discretion of experiences of treating physicians. In this study, the presently available treatment and diagnostic modalities with pros and cons of each of them were reviewed.”
“The ability to detect and quantify proteins of individual cells in high throughput is of enormous biological and clinical relevance. Most methods currently in use either require the measurement of large cell populations or are limited to the investigation of few cells at a time. In this report, we present the combination of a polydimethylsiloxane-based Bafilomycin A1 research buy microfluidic device to a matrix-assisted laser desorption

ionization time-of-flight mass spectrometer (MALDI-TOF-MS) that allows the detection of as few as 300 molecules at the peptide level and similar to 10(6) to 10(7) molecules at the protein level. Moreover, we performed an immunoassay with subsequent MALDI-TOF-MS to capture and detect insulin immobilized on a surface (similar to 0.05 mm(2)) in this device with a detection

limit of 10(6) insulin molecules. This microfluidic-based approach therefore begins to approach the sample handling and sensitivity requirements for MS-based single-cell analysis of proteins and peptides and holds the potential for easy parallelization of immunoassays and other highly sensitive protein analyses.”
“Decision-making Stem Cells & Wnt inhibitor is strongly influenced by the counterfactual anticipation of personal regret and relief, through a learning process involving the ventromedial-prefrontal cortex. We previously reported that observing the regretful outcomes of another’s choices reactivates the regret-network. Here we extend those findings by investigating whether this resonant mechanism also underpins interactive-learning from others’ previous outcomes. In this functional-Magnetic-Resonance-Imaging study 24 subjects either played a gambling task or observed another player’s risky/non-risky choices and resulting outcomes, thus experiencing personal or shared regret/relief for risky/non-risky decisions. Subjects’ risk-aptitude in subsequent choices was significantly influenced by both their and the other’s previous outcomes.

The main reason for the development of these learn more cysts might be the accompanying inflammation of the lymphoma.\n\nLittle is known about the imaging features of mediastinal cysts caused by lymphoma. Plain thymic cysts are normally homogenous on T1- and T2-weighted images. Hodgkin’s lymphoma might

be homogenous on T1-weighted images and is mostly inhomogenous on T2-weighted images.\n\nIn case of inhomogenous cysts with contrast-enhancing septation, one should consider the diagnosis of an associated neoplasm. (C) 2012 Elsevier GmbH. All rights reserved.”
“The delivery of factors secreted by adipose stromal cells (ASC) to the brain may be a viable neuroprotective therapeutic option. In this study, we investigated the bioactivity of ASC-conditioned medium (ASC-CM) in glutamate-induced neurotoxicity

and found that the ASC-CM significantly blocked glutamate neurotoxicity. We identified the brain-derived neurotrophic factor (BDNF) in the ASC-CM by using Western blot and demonstrated that this activity was critical for the neuroprotective effect of ASC-CM in excytotoxicity models. Furthermore, inactivating BDNF also attenuated the suppression by ASC-CM of glutamate-induced caspase-3 activity, but not p38 phosphorylation. These findings suggest that among ASC secrete a potent combination of factors, BDNF play a selleck chemical major role in neuroprotection against excytotoxicity. (c) 2009 Elsevier Ireland Ltd. All rights reserved.”
“Canonical WNT signaling activation leads to transcriptional up-regulation of FGF ligand, Notch ligand, non-canonical WNT ligand, WNT antagonist, TGF beta antagonist, and MYC. Non-canonical WNT signals inhibit canonical WNT signaling by using MAP3K7-NLK signaling cascade. Transmembrane Transporters inhibitor Hedgehog up-regulates Notch ligand, WNT antagonist, BMP antagonists, and MYCN. TGF beta up-regulates non-canonical WNT ligand, CDK inhibitors, and NANOG, while BMP up-regulates Hedgehog ligand. Based on these mutual regulations, WNT,

FGF, Notch, Hedgehog, and TGF beta/BMP signaling cascades constitute the stem-cell signaling network, which plays a key role in the maintenance or homeostasis of pluripotent stem cells and cancer stem cells. Human embryonic stem cells (ESCs) are supported by FGF and TGF beta/Nodal/Activin signals, whereas mouse ESCs by LIF and canonical WNT signals. Combination of TGF beta inhibitor and canonical WNT activator alter the character of human induced pluripotent stem cells (iPSCs) from human ESC-like to mouse ESC-like. Fine-tuning of WNT, FGF, Notch, TGF beta/BMP, and Hedgehog signaling network by using small-molecule compounds could open the door for regenerative medicine utilizing pluripotent stem cells without tumorigenic potential. Because FGF, Hedgehog, TGF beta, and non-canonical WNT signals synergistically induce EMT regulators, such as Snail (SNAI1), Slug (SNAI2), TWIST, and ZEB2 (SIP1), tumor-stromal interaction at the invasion front aids cancer stem cells to acquire more malignant phenotype.