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The article investigates why Georgian and Moldovan think-tanks have not emulated effective forms of advocacy in relations with the EU that their Ukrainian counterparts have established, namely a liaison office in Brussels. The reason is not the cost but rather the presence of alternative communication channels, high-level personal contacts and think-tanks' focus on organizational survival. Better connectivity and new means of communication make the presence of a Brussels hub less crucial for regional think-tanks. Our research shows that there is often limited collaboration amongst think-tanks at the national level, which negatively affects opportunities for transnational advocacy of Eastern Partnership (EaP) think-tanks in relations with EU institutions. [ABSTRACT FROM AUTHOR]

Polyphenols have attracted a lot of global attention due to their diverse biological actions against cancer, obesity, and cardiovascular diseases. Although extensive research has been carried out to elucidate the mechanisms of pleiotropic actions of polyphenols, this remains unclear. Lipid rafts are distinct nanodomains enriched in cholesterol and sphingolipids, present in the inner and outer leaflets of cell membranes, forming functional platforms for the regulation of cellular processes and diseases. Recent studies focusing on the interaction between polyphenols and cellular lipid rafts shed new light on the pleiotropic actions of polyphenols. Polyphenols are postulated to interact with lipid rafts in two ways: first, they interfere with the structural integrity of lipid rafts, by disrupting their structure and clustering of the ordered domains; second, they modulate the downstream signaling pathways mediated by lipid rafts, by binding to receptor proteins associated with lipid rafts, such as the 67 kDa laminin receptor (67LR), epidermal growth factor receptor (EGFR), and others. This study aims to elaborate the mechanism of interaction between polyphenols and lipid rafts, and describe pleiotropic preventive effects of polyphenols. [ABSTRACT FROM AUTHOR]

Caveolae are flask‐shaped invaginations of the cell membrane rich in cholesterol and sphingomyelin, with caveolin proteins acting as their primary structural components that allow compartmentalization and orchestration of various signalling molecules. In this review, we discuss how pleiotropic functions of caveolin‐1 (Cav1) and its intricate roles in numerous cellular functions including lipid trafficking, signalling, cell migration and proliferation, as well as cellular senescence, infection and inflammation, are integral for normal development and functioning of skin and its appendages. We then examine how disruption of the homeostatic levels of Cav1 can lead to development of various cutaneous pathophysiologies including skin cancers, cutaneous fibroses, psoriasis, alopecia, age‐related changes in skin and aberrant wound healing and propose how levels of Cav1 may have theragnostic value in skin physiology/pathophysiology. [ABSTRACT FROM AUTHOR]

Central centrifugal cicatricial alopecia (CCCA) has an unknown mechanism. Analyzing other scarring diseases (lichen planopilaris, fibrotic kidney disease and scleroderma) may help to clarify the mechanism of scarring in CCCA. These diseases were chosen for comparison due to either their location of disease (skin or scalp specifically), or prominence in patients of African descent. Genetics, possible triggers, an autoimmune lymphocytic response, and epithelial to mesenchymal transition are potentially involved. Possible common pathways in scarring diseases and a better understanding of the CCCA mechanism will lead to further research into the pathogenesis and potential treatments of CCCA. [ABSTRACT FROM AUTHOR]

Limiting lung disease: Fibrotic foci that form during idiopathic pulmonary fibrosis (IPF), a type of progressive and fatal interstitial lung disease, alter lung architecture, leading to cell death and loss of lung function. Marudamuthu et al. developed a caveolin-1–derived peptide, CSP7, that inhibited apoptosis of alveolar epithelial progenitor cells and activation of fibrotic lung fibroblasts. When delivered to three mouse models of lung fibrosis, CSP7 reduced extracellular matrix deposition, promoted epithelial cell survival, and improved lung function. CSP7 was also effective when administered ex vivo to lung tissue or cells isolated from people with end-stage IPF. These results support further development of CSP7 as a potential treatment. Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease with a median 5-year survival of ~20%. Current U.S. Food and Drug Administration–approved pharmacotherapies slow progression of IPF, providing hope that even more effective treatments can be developed. Alveolar epithelial progenitor type II cell (AEC) apoptosis and proliferation, and accumulation of activated myofibroblasts or fibrotic lung fibroblasts (fLfs) contribute to the progression of IPF. Full-length caveolin-1 scaffolding domain peptide (CSP; amino acids 82 to 101 of Cav1: DGIWKASFTTFTVTKYWFYR) inhibits AEC apoptosis and fLf activation and expansion and attenuates PF in bleomycin (BLM)–induced lung injury in mice. Like full-length CSP, a seven–amino acid deletion fragment of CSP, CSP7 (FTTFTVT), demonstrated antifibrotic effects in murine models of lung fibrosis. When CSP7 was administered during the fibrotic phase in three preclinical models [single-dose BLM, repeated-dose BLM, and adenovirus expressing constitutively active transforming growth factor–β1 (Ad-TGF-β1)–induced established PF], CSP7 reduced extracellular matrix (ECM) markers characteristic of PF, increased AEC survival, and improved lung function. CSP7 is amenable to both systemic (intraperitoneal) or direct lung delivery in a nebulized or dry powder form. Furthermore, CSP7 treatment of end-stage human IPF lung tissue explants attenuated ECM production and promoted AEC survival. Ames testing for mutagenicity and in vitro human peripheral blood lymphocyte and in vivo mouse micronucleus transformation assays indicated that CSP7 is not carcinogenic. Together, these findings support the further development of CSP7 as an antifibrotic treatment for patients with IPF or other interstitial lung diseases. [ABSTRACT FROM AUTHOR]

Counteracting calpain: During fibrosis, myofibroblasts produce extracellular matrix that accumulates and impairs tissue function. Kim et al. found that transforming growth factor–β induced translation of calpain 9, a cysteine protease, which mediated myofibroblast differentiation. Mice lacking calpain 9 were protected from experimentally induced fibrosis in the heart, lung, and liver. The authors identified a common calpain 9 loss-of-function mutation in people that was not associated with markers of intolerance. This study suggests that targeting calpain 9 could have therapeutic potential for inhibiting fibrosis. Fibrosis is a common pathologic outcome of chronic disease resulting in the replacement of normal tissue parenchyma with a collagen-rich extracellular matrix produced by myofibroblasts. Although the progenitor cell types and cellular programs giving rise to myofibroblasts through mesenchymal transition can vary between tissues and diseases, their contribution to fibrosis initiation, maintenance, and progression is thought to be pervasive. Here, we showed that the ability of transforming growth factor–β (TGFβ) to efficiently induce myofibroblast differentiation of cultured epithelial cells, endothelial cells, or quiescent fibroblasts is dependent on the induced expression and activity of dimeric calpains, a family of non-lysosomal cysteine proteases that regulate a variety of cellular events through posttranslational modification of diverse substrates. siRNA-based gene silencing demonstrated that TGFβ-induced mesenchymal transition of a murine breast epithelial cell line was dependent on induction of expression of calpain 9 (CAPN9), an isoform previously thought to be restricted to the gastrointestinal tract. Mice lacking functional CAPN9 owing to biallelic targeting of Capn9 were viable and fertile but showed overt protection from bleomycin-induced lung fibrosis, carbon tetrachloride–induced liver fibrosis, and angiotensin II–induced cardiac fibrosis and dysfunction. A predicted loss-of-function allele of CAPN9 is common in Southeast Asia, with the frequency of homozygosity matching the prediction of Hardy-Weinberg equilibrium. Together with the highly spatially restricted pattern of CAPN9 expression under physiologic circumstances and the heartiness of the murine knockout, these data provide a strong signature for tolerance of therapeutic strategies for fibrosis aimed at CAPN9 antagonism. [ABSTRACT FROM AUTHOR]

Following skin wounding, the healing outcome can be: regeneration, repair with normal scar tissue, repair with hypertrophic scar tissue or the formation of keloids. The role of chemical factors in wound healing has been extensively explored, and while there is evidence suggesting the role of mechanical forces, its influence is much less well defined. Here, we provide a brief review on the recent progress of the role of mechanical force in skin wound healing by comparing laboratory mice, African spiny mice, fetal wound healing and adult scar keloid formation. A comparison across different species may provide insight into key regulators. Interestingly, some findings suggest tension can induce an immune response, and this provides a new link between mechanical and chemical forces. Clinically, manipulating skin tension has been demonstrated to be effective for scar prevention and treatment, but not for tissue regeneration. Utilising this knowledge, specialists may modulate regulatory factors and develop therapeutic strategies to reduce scar formation and promote regeneration. [ABSTRACT FROM AUTHOR]

The imbalance of Th17/Treg cells plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Caveolin-1 (Cav-1) has been regarded as a potential critical regulatory protein in pathological mechanisms of chronic inflammatory respiratory diseases. Therefore, we investigated whether the loss of Cav-1 is involved in the homeostasis of Th17/Treg cells in COPD. We examined the expressions of plasma Cav-1 and circulating Th17, Treg cells, and the related cytokines in patients with COPD. Enzyme-linked immunosorbent assay (ELISA) analyses showed a significant reduction of plasma Cav-1 levels in patients with stable COPD (SCOPD) and acutely exacerbated COPD (AECOPD) compared to smokers without COPD. This loss was associated with an increase in frequency of Treg and decreased in frequency of Th17 cells. To further identify the role of Cav-1, we studied the effects of Cav-1 overexpression or downregulation on frequencies of Treg and Th17 cells in peripheral blood mononuclear cells (PBMCs) from subjects. Interestingly, small interfering RNA (siRNA) downregulation of Cav-1 was accompanied by an augmentation of Treg and reduction of Th17 expression. Together, our study demonstrated that the loss of Cav-1 contributed to the imbalance of Th17/Treg cells in patients with COPD. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis ( IPF) is a destructive inflammatory disease with limited therapeutic options. Inflammation plays an integral role in the development of pulmonary fibrosis. Unresolved inflammatory responses can lead to substantial tissue injury, chronic inflammation, and fibrosis. The resolvins are a family of endogenous ω-3 fatty acid derived-lipid mediators of inflammation resolution. Resolvin D1 (RvD1) displays potent anti-inflammatory, pro-resolving activity, without causing immunosuppression. Its epimer, 17(R)-resolvin D1 (17(R)-RvD1), exhibits equivalent functionality to RvD1. In addition, 17(R)-RvD1 is resistant to rapid inactivation by eicosanoid oxidoreductases. In the present study, we tested the hypothesis that 17(R)-RvD1 can provide a therapeutic benefit in IPF by reducing inflammation and pulmonary fibrosis, while leaving the normal immune response intact. Mice were exposed to bleomycin ( BLM) via micro-osmotic pump to induce pulmonary fibrosis, and were then treated with 17(R)-RvD1 or vehicle by intraperitoneal injection. Administration of 17(R)-RvD1 from the start of BLM treatment attenuated neutrophil alveolar infiltration, lung collagen content, and Interleukin-1 β ( IL-1 β), transforming growth factor- β1 ( TGF- β1), connective tissue growth factor ( CTGF), and type I collagen mRNA expression, along with subsequent reduction in histologically detectable fibrosis. The 17(R)-RvD1-induced infiltration of inflammatory cells was inhibited by an antagonist of lipoxin A4 receptor/formyl peptide receptor 2 ( ALX/ FPR2). The administration of 17(R)-RvD1 at the later fibrotic stage also improved the lung failure. These results suggest that 17(R)-RvD1 attenuates pulmonary fibrosis by promoting the resolution of neutrophilic inflammation and also provides pulmonary restoration. These data highlight the therapeutic potential of 17(R)-RvD1 in the management of this intractable disease. [ABSTRACT FROM AUTHOR]

Previous studies have shown that protease-activated receptors (PARs) play an important role in various physiological processes. In the present investigation, we determined the expression of PARs on human lung fibroblasts (HLF-1) and whether they were involved in cellular differentiation and pro-inflammatory cytokine and prostaglandin (PGE2) secretion. PAR-1, PAR-2, PAR-3, and PAR-4 were detected in fibroblasts using RT-PCR, immunocytochemistry, and flow cytometry. Increased expression of PAR-4, but not other PARs, was observed in fibroblasts stimulated with phorbol myristate acetate. The archetypical activators of PARs, namely, thrombin and trypsin, as well as PAR-1 and PAR-2 agonist peptides, stimulated transient increases in intracellular Ca2+, and promoted increased α-smooth muscle actin expression. The proteolytic and peptidic PAR activators also stimulated the release of IL-6 and IL-8, as well as PGE2, with a rank order of potency of PAR-1 > PAR-2. The combined stimulation of PAR-1 and PAR-2 resulted in an additive release of both IL-6 and IL-8. In contrast, PAR-3 and PAR-4 agonist peptides, as well as all the PAR control peptides examined, were inactive. These results suggest an important role for PARs associated with fibroblasts in the modulation of inflammation and remodeling in the airway. [ABSTRACT FROM AUTHOR]

The interstitial lung diseases (ILD) include a large number of chronic, progressive, irreversible respiratory disorders involving pulmonary fibrosis, the most common of which are idiopathic pulmonary fibrosis and scleroderma lung disease (SSc ILD). Because bleomycin causes lung fibrosis when used in cancer chemotherapy, it is used to model human ILD in rodents. In most studies, bleomycin has been delivered directly into the lung by intratracheal or intraoral administration. Here we have compared the effects in mice of bleomycin delivered directly into the lungs (direct model) or systemically using osmotic minipumps (pump model) to determine which more closely resembles human ILD. The pump model is more similar to human SSc ILD in that: 1) lung injury/fibrosis is limited to the subpleural portion of the lung in the pump model and in SSc ILD, whereas the entire lung is affected in the direct model; 2) conversely, there is massive inflammation throughout the lung in the direct model, whereas inflammation is limited in the pump model and in SSc ILD; 3) hypertrophic type II alveolar epithelial cells are present at high levels in SSc ILD and in the pump model but not in the direct model; and 4) lung fibrosis is accompanied by dermal fibrosis. The pump model is also move convenient and humane than the direct model because there is less weight loss and mortality. [ABSTRACT FROM AUTHOR]

This document provides the abstracts of papers presented at the 2013 Annual Meeting of the American College of Rheumatology (ACR) which cover topics such as rheumatoid arthritis, systemic lupus erythematosus and innate immunity.

Diffuse systemic sclerosis (SSc) is a fatal autoimmune disease characterized by an excessive ECM deposition inducing a loss of function of skin and internal organs. Apoptosis is a key mechanism involved in all the stages of the disease: vascular damage, immune dysfunction, and fibrosis. The purpose of this paper is to gather new findings in apoptosis related to SSc, to highlight relations between apoptosis and fibrosis, and to identify new therapeutic targets. [ABSTRACT FROM AUTHOR]

The single-cell Raman spectra of human Burkitt's lymphoma cells (CA46) including cells treated with different doses of paclitaxel and controls without paclitaxel can be detected by confocal micro-Raman spectroscopy. It shows that the Raman bands at 1094 cm-1 assigned to the symmetric stretching vibration mode of O-P-O in the DNA backbone, 1338 cm-1 and 1578 cm-1 due to adenine and guanine of DNA all decrease in intensity with increasing drug dose. On the contrary, the intensity of peaks at 1257 cm-1 due to characteristic vibration of α-helix of Amide III and 1658 cm-1 due to characteristic vibration of α-helix of Amide I both increases with increasing drug dose. Multivariate statistical methods, such as Principle Components Analysis (PCA) and Linear Discriminant Analysis (LDA) were employed to discriminate normal lymphoma cells (CA46) and cells treated with different doses of paclitaxel. It was found that the sensitivity and specificity of differentiating the treated and untreated cell groups increase with drug doses and approach 100% for the high drug dose, consistent with the perception that the cytotoxicity increases with drug dose. These results suggest that Raman spectroscopy combined with multivariate analysis could become a useful tool for assessing the cytotoxicity of drugs such as paclitaxel on human lymphoma cells. [ABSTRACT FROM AUTHOR]

Lung fibrosis involves the overexpression of ECM proteins, primarily collagen, by a smooth muscle actin (ASMA)-positive cells. Caveolin-l is a master regulator of collagen expression by cultured lung fibroblasts and of lung fibrosis in vivo. A peptide equivalent to the caveolin-l scaffolding domain (CSD peptide) inhibits collagen and tenascin-C expression by normal lung fibroblasts (NLF) and fibroblasts from the fibrotic lungs of scleroderma patients (SLF). CSD peptide inhibits ASMA expression in SLF but not NLF. Similar inhibition of collagen, tenascin-C, and ASMA expression was also observed when caveolin- I expression was upregulated using adenovirus. These observations suggest that the low caveolin-l levels in SLF cause their overexpression of collagen, tenascin-C, and ASMA. In mechanistic studies, MEK, ERK, JNK, and Akt were hyperactivated in SLF, and CSD peptide inhibited their activation and altered their subcellular localization. These studies and experiments using ldnase inhibitors suggest many differences between NLF and SLF in signaling cascades. To validate these data, we determined that the alterations in signaling molecule activation observed in SLF also occur in fibrotic lung tissue from scieroderma patients and in mice with bleomycin-induced lung fibrosis. Finally, we demonstrated that systemic administration of CSD peptide to bleomycin-treated mice blocks epithelial cell apoptosis, inflammatory cell infiltration, and changes in tissue morphology as well as signaling molecule activation and collagen, tenascin-C, and ASMA expression associated with lung fibrosis. CSD peptide may be a prototype for novel treatments for human lung fibrosis that act, in part, by inhibiting the expression of ASMA and ECM proteins. [ABSTRACT FROM AUTHOR]

This study was aimed to evaluate the antioxidant abilities of water (SGWE), 50% ethanolic (SGE50) and 95% ethanolic (SGE95) extracts from the stem of Graptopetalum paraguayense, and the extract with the highest antioxidant activity was assayed for its inhibitory effect on proliferation of human hepatoma (Hep G2) cell line. Antioxidant abilities of extracts were assessed their radical-scavenging abilities and effects on Fe/ascorbate-induced lipid peroxidation in a liposome model system. The results of this study showed that antioxidant activities were increased with the increase of the extracts concentrations, and the activities correlated with both the total phenol and anthocyanin contents. A comparison of the 50% inhibition concentration (IC(50)) values of different antioxidant reactions revealed that SGWE was the more effective at scavenging superoxide anion radical and preventing lipid peroxidation than SGE50 and SGE95 (p < 0.05). The flow cytometry results indicated that SGWE lowered cell viability, and induced G1 phase arrest and apoptosis in Hep G2 cells. These results demonstrated the antioxidatant and anti-hepatoma potential of stem of Graptopetalum paraguayense. [ABSTRACT FROM AUTHOR]

This study was aimed to evaluate the antioxidant abilities of water (SGWE), 50% ethanolic (SGE50) and 95% ethanolic (SGE95) extracts from the stem of Graptopetalum paraguayense, and the extract with the highest antioxidant activity was assayed for its inhibitory effect on proliferation of human hepatoma (Hep G2) cell line. Antioxidant abilities of extracts were assessed their radical-scavenging abilities and effects on Fe/ascorbate-induced lipid peroxidation in a liposome model system. The results of this study showed that antioxidant activities were increased with the increase of the extracts concentrations, and the activities correlated with both the total phenol and anthocyanin contents. A comparison of the 50% inhibition concentration (IC50) values of different antioxidant reactions revealed that SGWE was the more effective at scavenging superoxide anion radical and preventing lipid peroxidation than SGE50 and SGE95 (p < 0.05). The flow cytometry results indicated that SGWE lowered cell viability, and induced G1 phase arrest and apoptosis in Hep G2 cells. These results demonstrated the antioxidatant and anti-hepatoma potential of stem of Graptopetalum paraguayense. [ABSTRACT FROM AUTHOR]

Activated fibroblasts, or myofibroblasts, are crucial players in tissue remodeling, wound healing, and various fibrotic disorders, including interstitial lung fibrosis associated with scleroderma. Here we characterize the signaling pathways in normal lung fibroblasts exposed to thrombin as they acquire two of the main features of myofibroblasts: smooth muscle (SM) α-actin organization and collagen gel contraction. Our results show that the small G protein Rho is involved in lung myofibroblast differentiation. Thrombin induces Rho-[sup 35]S-labeled guanosine 5'-O-(3thiotriphosphate) binding in a dose-dependent manner. It potently stimulates Rho activity in vivo and initiates protein kinase C (PKC)-∈-Rho complex formation. Toxin B, which inactivates Rho by ADP ribosylation, inhibits thrombin-induced SM α-actin organization, collagen gel contraction, and PKC-∈-SM α-actin and PKC-e-RhoA coimmunoprecipitation. However, it has no effect on PKC-e activation or translocation of PKC-∈ to the membrane. Overexpression of constitutively active PKC-∈ and constitutively active RhoA induces collagen gel contraction or SM α-actin organization, whereas, individually, they do not perform these functions. We therefore conclude that the contractile activity of myofibroblasts induced by thrombin is mediated via PKC-∈- and RhoA-dependent pathways and that activation of both of these molecules is required. We postulate that PKC-∈-RhoA complex formation is an early event in thrombin activation of lung fibroblasts, followed by PKC-∈-SM α-actin coimmunoprecipitation, which leads to the PKC-∈-RhoA-SM α-actin ternary complex formation. [ABSTRACT FROM AUTHOR]

Purpose. We previously reported that in patient tumors the expression of the mdr1 p-glycoprotein (Pgp) resulted in a lower paclitaxel-induced inhibition of DNA precursor incorporation, but a higher apoptosis ( Clin. Cancer Res. 4:2949-2955, 1998). The present study was to evaluate these findings in an experimental system where the Pgp effect can be studied without confounding factors such as the intra- and inter-tumor heterogeneity associated with patient tumors. Methods. To separate the effect of Pgp on intracellular paclitaxel accumulation from its effects on drug sensitivity, we compared the drug activity at various extracellular and intracellular drug concentrations using the human breast MCF7 tumor cells and its mdr1-transfected variant BC19 cells. Results. Compared to MCF7 cells, BC19 cells showed a 9-fold higher Pgp level and >13-fold higher mdr1 expression. Intracellular paclitaxel accumulation was 80-130% lower in BC19 cells when the extracellular concentrations were ≤100 nM, but the difference was reduced to <15% differences at higher extracellular concentrations of ≥1,000 nM. For the G2/M block effect MCF7 cells were 43-fold more sensitive than BC19 cells at equal extracellular concentration, and 3.5-fold more sensitive at comparable intracellular concentrations. On the contrary, BC19 cells were more sensitive to the apoptotic effect; BC19 cells showed equal or higher apoptosis compared to MCF7 cells at extracellular concentrations above 100 nM, and a 30-100% higher apoptosis at comparable intracellular concentrations. Conclusions. These results confirm our previous observations in patient tumors and indicate that enhanced Pgp expression is associated with enhanced sensitivity to the apoptotic effect of paclitaxel and reduced sensitivity to its G2/M block effect, via yet-unknown mechanisms that are unrelated to the effect of Pgp on intracellular drug accumulation. [ABSTRACT FROM AUTHOR]

Shows that apoptosis induced by ultraviolet irradiation or 80 mug/ml etoposide correlates with early transient polymerization and later depolymerization of filamentous actin and changes in visible microfilament organization. Regulation of overall cellular morphology; Apoptotic body formation site; coordination of cellular motility.

The effect of the transmethylation inhibitor 3-deazaadenosine on transcription levels of genes associated with apoptosis was investigated in HL-60 cells. After incubation of HL-60 cells with 100 μM 3-deazaadenosine for 45 min., a schedule known to perturb transmethylation metabolites and initiate apoptosis in these cells, a 50% decrease in c-myc and a 50% increase in bcl-2 RNA steady-state levels compared to control cells were observed. Transcription levels of c-myc continued to decrease after extended exposure to 3-deazaadenosine, while bcl-2 mRNA levels dropped to 25% and 30% below those in control cells after 1.5 hr and 3 hr, respectively. The expression levels of the bcl-2 related bax gene, showed a similar pattern as bcl-2; a 60% increase was initially measured, but after 1.5 and 3 hr, bax transcripts were 80% and 70% respectively, of those found in untreated cells. Another bcl-2 related gene, bcl-x, was previously reported to generate two transcripts in human cells. The long variant bcl-x1 acts as bcl-2, while the short form bcl-xs induces apoptosis. We were unable to detect bcl-xs transcripts in untreated and 3-deazaadenosine treated cells by the highly sensitive reverse transcriptase polymerase chain reaction method. This suggests that this gene product may not be involved in 3-deazaadenosine induced apoptosis in HL-60 cells. Bcl-x1 mRNA levels, however, slowly decreased with about 50% after 1.5 or 3 hr 3-deazaadenosine treatment. It is concluded that 3-deazaadenosine initiated apoptosis affects c-myc, bcl-2, bax and bcl-x1 mRNA levels. [ABSTRACT FROM AUTHOR]