The membranes were blocked, washed and incubated with specific primary antibodies. The primary antibody incubation was fol lowed by incubation with HRP conjugated secondary antibodies. The bands were detected with an enhanced chemiluminescence assay. ELISA Various ovarian cancer those cell lines were seeded in 60 mm plates and incubated with Corilagin or DMSO. Culture supernatants were harvested after 1, 2, and 3 days to measure the concen tration of TGF B1. Hey cells were seeded in 96 well plates and incubated with Corilagin, Paclitaxel, or DMSO the next day. Culture supernatants were harvested at 48 h to measure the concentration of TGF B1. SRB was used to detect the effects of Corilagin and Paclitaxel on the proliferation of ovarian cancer cells.

The concentration of TGF B1 was measured by ELISA according to the manufacturers instructions. mice. The SKOv3ip cells were injected subcutaneously. Tumors were measured twice a week, and tumor volumes were calculated using the formula TV /2, where L represents the longer diameter and W represents the shorter diam eter. When palpable tumors had grown to a diameter of 0. 3 0. 5 cm, the mice were divided into four groups of six to eight, and each group received an intraperi toneal injection of either DMSO or 5, 10, or 15 mg/kg of Corilagin. The doses of Corilagin Growth of xenografts in nu/nu mice All animal experiments were carried out in accor dance with an animal protocol approved by the Insti tutional Animal Care and Use Committee of the Shanghai Tumor Institute.

The effect Batimastat of Corilagin on the in vivo growth of ovarian cancer xenograft tumors was evaluated using xenografts of the human ovarian cancer cell line SKOv3ip in Balb/c nu/nu used were in reference to the animal experiments of Hau DKs group. The mice were treated three times per week for four weeks and were then sacrificed. Statistical analysis All data were subjected to statistical analysis and were reported as the mean standard deviation. The criterion for statistical significance was taken as P 0. 05 using a two tailed t test and the count data were tested using chi square criterion comparing the parameters frequency of parameters. The analyses were performed using SPSS 15. 0 software. Results Corilagin inhibits the growth of ovarian cancer cell lines in vitro and in vivo Ovarian cancer cell lines and normal OSE cells were used to examine the effects of Corilagin in cell culture. Corilagin demonstrated clear inhibition of ovarian cancer cell growth but had much lower cytotoxicity in normal OSE cells, with IC50s of approximately 160 uM. To determine if Corilagin had the same effect in vivo, Corilagin was delivered by intraperitoneal injection into mice bearing SKOv3ip xenografts.

The X2 test and the Fishers exact test were used to test associations between genotypes and categorical vari ables describing the clinico pathologic features of the study population. Survival curves were plotted seriously using the Kaplan Meier and compared using the log rank test. The Cox proportional hazards model was used for multivariate analysis to estimate and test demographic characteristics, clinical and genetic features for their associations with OS. In this exploratory study, no formal correction for mul tiple comparisons was adopted. However, all the following variables were included in multivariate Cox model age, sex, ECOG performance status, weight loss, anemia, albu min level, CEA level, tumor grading, histologic subtype according to Laurens classification, tumor location, liver involvement, presence of peritoneal carcinomatosis, number of metastatic sites and response to first line chemotherapy.

Assuming a 20% lowest frequency for an unfavorable genotype, 157 events would allow to detect an Hazard Ratio of 1. 75 associated with this group. All results were considered significant at two sided p. 05 value. All analyses were performed by using the MedCalc software version 11. 1. Results Characteristics of patients and genotyping One hundred sixty one patients were analyzed. All of them received first and second line chemotherapy and died after gastric cancer progression. First line chemother apy was oxaliplatin or cisplatin plus a fluoropyrimidne in 150 patients, or bolus/infusional 5 Fluorouracil in 11 patients.

Second line chemotherapy was 5 Fluorouracil coupled with cisplatin or oxaliplatin in 48 patients, with CPT 11 in 45 patients, with anthracycline in 33 patients, with paclitaxel or docetaxel in 25 patients, with VP 16 in 10 patients. Median survival time in the whole group was 9. 4 months. Carriers of the rs1800795 G/G, G/C and C/C geno types were 74, 68 and 19, respectively. Carriers of the rs8192284 A/A, A/C and C/C genotypes were 58, 73 and 30, respectively. These frequencies did not show deviation from Hardy Weinberg equilibrium and they are comparable with frequencies commonly observed in Caucasian populations. Details of the characteristics of enrolled patients to gether with their distribution according to rs1800795 and rs8192284 genotypes are shown in Table 1. No significant association was observed except for liver involvement and rs8192284 genotypes.

In particular, rs8192284 C/C car riers were prevalent in patients with liver metastases, while rs8192284 A/A carriers were prevalent in patients without liver metastases. Survival analyses Survival Dacomitinib curves of carriers of the rs1800795 and rs8192284 genotypes are shown in Figure 1. In carriers of the rs1800795 G/G, G/C and C/C genotypes, median survival times were 8. 4, 11 and 12. 6 months, respectively. In carriers of the rs8192284 A/A, A/C and C/C genotypes median survival times were 11. 7, 10. 1 and 8.

The family of HDACi represents a novel approach in oncological research. In defined predominantly haem atological tumour entities, HDACi have already passed the selleckchem CHIR99021 stage of experimental research and been investigated clinically. Regarding PDAC, promising results have been shown using SAHA, TSA, butyrate and some other histone deacetylase inhibitors in experimental studies. Belinostat is a novel member of the family with a distinct pan HDAC inhibitory effect. It has been shown to be strongly effective in experimental settings of ovarian, bladder and colon cancer, as well as haemato logical tumour entities. Consecutive clinical trials have proven an anti tumour effect of belinostat as a monotherapy in T cell lymphomas and thymomas.

In addition, belinostat has demonstrated beneficial effects in combination with other anti cancer drugs for the treatment of ovarian and bladder cancer, CUP, multiple myeloma and acute myeloid leukaemia. Despite these findings, no data are available concerning belinostat in the context of PDAC treatment. Consequently, in the present study, the efficacy of belinostat for PDAC treat ment was investigated in experimental in vitro and in vivo settings for the first time. Comparable to the results of previous studies in blad der, colorectal or hepatocellular carcinoma, we found a strong dose dependent antiproliferative ac tivity of belinostat in three pancreatic cancer cell lines with an IC50 concentra tion in the nanomolar range, similar to other tumour entities. This antiproliferative effect can be explained by a strong proapoptotic activity in pancreatic cancer cells, demonstrated by annexinV/propidium iodide staining.

This is in line with other studies on AML and hepatocellular carcinoma cells, underlining that apoptosis induction is an important mechanism of the anti tumourous effect of HDACi, and particularly beli nostat. As apoptosis induction is an important mechan ism of anti cancer chemotherapy, we tested the influence of concomitant use of belinostat and gemcita bine. As described in studies with other HDACi like tri chostatin A and 4 phenylbutyrate , the combination of gemcitabine and belinostat strongly enhanced the proapoptotic effects of each substance alone. This may be due to the expression of proapoptotic proteins like Caspase 8 and Bid, and activation of the gemcitabine mediated JNK pathway.

Increase in histone H4 acetylation has been shown to be helpful in monitoring belinostat activity. Conse quently, we examined belinostat dependent expression of acH4 in PDAC cells. Acetylation of H4 was increased in all cell lines tested, confirming the inhibitory effect of belinostat on HDAC activity in pancreatic cancer cells. Cyclin dependent kinase inhibitor Brefeldin_A p21Cip1/Waf1 is a key protein participating in cell cycle regulation.

T24 and UMUC3 cells were grown in 25 cm2 tissue culture flasks sellckchem and treated with 0. 5, 1. 0, 2. 5, 5. 0 mM valproate, and 1. 0 or 5. 0 uM SAHA for three days. At 5 uM SAHA RNA yields were insuffi cient for analysis indicating a cytotoxic dose. The qPCR results are presented in Figure 3. TSP1 expression in the UMUC3 cells was significantly increased at doses of 1. 0 mM and higher and was over 8 fold higher relative to control at 5 mM. SAHA at 1 uM increased TSP1 ex pression more than three fold as well. Similar results were obtained for the T24 cell line with a dose dependent increase in TSP1 expression, and was signifi cant at 0. 5 mM and higher concentrations of valproate reaching 6 fold levels at 5 mM. SAHA induced TSP1 ex pression almost four fold in the T24 cells.

Discussion The primary goal of our study was to investigate the effects of valproate on bladder cancer cells and provide a possible mechanism for these effects. First, we confirmed decreased proliferation with histone deacetylase inhibition in the two bladder cancer cell lines, T24 and UMUC 3. Second, we demonstrated that valproate increased TSP1 production, evidenced by increased mRNA expression. The UMUC 3 cell line also displayed profound morpho logical changes with valproate. The dendritic processes are consistent with urothelial umbrella cell differentiation. These data support the hypothesis that valproic acid exerts a negative effect on bladder cancer growth and shift to a more differentiated state. TSP1 expression has been noted to be lower in bladder cancer specimens and it is a potent anti angiogenic mediator.

Other work suggests that valproate acid is an inhibitor of angiogenesis through direct effects on endothelial cells. A connection between HDAC inhib ition and TSP1 expression has not been reported. Our in vitro work suggests that valproate acid may modify angio genesis in cancer by its action on TSP1 expression. The exophytic growth of bladder tumors is dependent on angiogenic support, inhibition of angiogenesis could slow growth and possibly kill bladder tumors. Valproate is a drug with a long clinical history for the treatment of seizures. The toxicity profile for valproate is acceptable for its possible use in chemoprevention of bladder cancer. The recommended therapeutic level of valproic acid for the treatment of seizures is generally accepted to be between 50 125 ug mL in humans.

At the high end this serum level is 0. 75 mM. A recent study looked at valproic acid induced proliferative changes in ovarian cancer cells Cytotoxic effects of valproic acid were noted above 2. 5 mM which AV-951 is consist ent with our findings. Changes in RNA expression do not necessarily lead to changes in protein levels and we did not assess TSP1 protein levels in this in vitro study.

All the TNBC cell lines exhibited high levels of Chk1 phosphorylated on Ser296 compared to the ER positive breast cancer cell lines. In the sensitive luminal breast selleck catalog cancer cell line SKBr3, the en dogenous levels of H2AX phosphorylated on Ser139 was much higher compared to all other cell lines. In the ovar ian cell lines, the sensitive A2780 and SKOV 3 as well as the resistant ES 2 cell line exhibited high levels of en dogenous pChk1. Chk1 was expressed in variable amounts across all eleven cell lines examined whilst the levels of Chk1 phosphorylated on the ATM ATR sites Ser317 and 345 was virtually undetectable. The increased levels of Chk1 and H2AX phosphorylation are consistent with underlying defects in DNA repair and or replication.

Analysis of other proteins associated with DNA replication or the DDR response did not identify a consistent mechanism for Chk1 activation. V158411 potentiates cytotoxic chemotherapy in TNBC and ovarian cancer cell lines The ability of V158411 to potentiate the cytotoxicity of a variety of cytotoxic chemotherapeutic drugs was assessed across a panel of luminal breast cancer and TNBC cell lines. V158411 effectively potentiated the growth inhibi tory activity of gemcitabine and cisplatin in the panel of p53 defective but not p53 proficient cell lines. As has been seen with other Chk1 inhibitors, the most robust potentiation was observed with gemcitabine across the range of cell lines. For gemcitabine, not only did V158411 reduce the EC50 of the chemotherapeutic agent but it also increased the fraction of cells killed.

In the ovarian carcinoma cell line SKOV 3, V158411 mod estly potentiated the cytotoxic activity of carboplatin and cisplatin but not oxaliplatin. Western blotting analysis revealed that all three platinum drugs increased the phosphorylation of Chk1 on Ser296 but only Carfilzomib the combination of cisplatin with V158411 robustly induced H2AX phosphorylation on Ser139. As well as exhibiting single agent activity against TNBC and ovarian cancer cell lines, V158411 potentiated the cytotoxicity of chemotherapeutic drugs in these tumor types suggesting that Chk1 inhibitors either alone or in combination could be a viable treatment option in these tumor types. Discussion Multiple Chk1 inhibitors are currently undergoing clinical testing in combination with a variety of cytotoxic chemo therapeutic agents for their ability to potentiate the anti V158411 there may be subsets of cancers for which a Chk1 inhibi tor, administered as a single agent, could be a useful thera peutic option. We postulated that cancers with underlying defects in tumor efficacy of the chemotherapy drugs whilst not in creasing the systemic toxicity of these drugs.

The 18,023 genes form the expression dataset were ranked by level table 5 of expression in FC com pared to na ve controls and plotted against the average coverage of H4K5ac 5 kb relative to the TSS. The level of gene expression was found to correlate to H4K5ac enrichment such that the highest expressed genes had the highest coverage for H4K5ac, while the least expressed genes had the lowest coverage. This applied to both groups regardless of training, suggesting that H4K5ac is a general feature of expressed genes. We also confirmed that H4K12ac correlated with the level of gene expression. There was no correlation between gene expression and IgG IP coverage. These results indicate a clear association between both H4K5ac and H4K12ac and gene expression.

We then identified genes acetylated above average and performed a cross wise comparison between experimental groups. Based on the average promoter read count of 45 in our dataset, we considered genes with more than 50 reads in the promoter as above average. From a total of 23,235 genes in the dataset, 7,103 genes were identified in the FC group, and 7,708 genes in the control. Using this criteria, 742 genes were specific for FC, 1,273 genes were specific for control, and 6,029 genes were common to both groups. We then looked at whether genes with above average H4K5ac after 2 days of CFC were also associated with H4K12ac after one session of CFC. Using an adjusted threshold of 10 reads in promoter due to the lower aver age coverage, approximately 9 reads in promoter, in the H4K12ac dataset, we identified 4,259 unique genes with above average H4K12ac, of which 2,772 genes over lapped with genes with above average H4K5ac in FC, and 2,846 genes with above average H4K5ac in controls.

2,440 genes over lapped all three groups using this criteria. The results of these analyses extend our findings that in control conditions most nucleosomes are not only acety lated for H4K5 above the average of all genes, but are also acetylated for H4K12. Batimastat Interestingly, nearly two thirds of genes with above average H4K12ac after one session of CFC was found to overlap with above average H4K5ac after 2 days of CFC or context. This suggests that the same set of genes, associated with H4K12ac and induced imme diately after CFC, may be upregulated following reinforced training, regardless of the associated histone acetylation used to identify the genes. It also suggests that the same set of genes may be activated after initial learning, during the formation of contextual fear memory, and after memory re trieval, independently of the CFC paradigm.

Homogenates were cleared by centrifugation at 4 C in a microcentrifuge. Proteins were denatured by boiling in SDS PAGE sample buffer containing b mercaptoethanol and resolved by SDS PAGE. Proteins the following site were then electro phoretically transferred to PVDF membranes and probed with appropriate antibody. In these studies, immunoreactive bands were visualized by chemilumine sence using ECL plus western blotting detection system and captured on photographic film with subsequent digitization of images using a scanner. Inten sity of bands on digitized images was quantified using Imagequant TL. Choice of a protein for normalization was challenging for these studies because long term denervation resulted in profound alterations in levels of many cellular proteins, which was readily appreciated on Coomassie Blue stained SDS page gels of skeletal muscle lysates.

Commonly used housekeeping genes such as b tubulin, a actin and GAPDH proved to be unreliable for animals with prolonged denervation. Therefore, we have used the intensity of a neighboring non specific band for nor malization. Antibodies that were used in these studies include, RCAN2, FOXO1, REDD2, Apo D, and anti b tubu lin. Data are shown as mean SEM, and differences among means were determined by ANOVA as above. Statistics For real time PCR and western blotting data, differ ences among means were determined using one way ANOVA with a Newman Keuls multiple comparison test post hoc to test for significance of differences between pairs of means. Linear regression analysis was used to test correlations.

Calculations were performed using Graphad Prism 4. 0c. Background Flavonoid 3,5 hydroxylases and flavonoid 3 hydroxylases are versatile enzymes that accept several phenylpropanoid substrates. Of particular interest for anthocyanin pigmentation is the 3,5 or 3 hydroxylation of naringenin and dihydrokaempferol. F35Hs and F3Hs compete for substrate recruitment and deliver their 35 or 3 OH products into the paral lel synthesis of delphinidin and cyanidin, the precur sors of blue and red anthocyanins in grape berries, respectively. Variation in anthocyanin profile within and between grape varieties is associated with differences in the ratio of F35H to F3H expression. Anthocyanin biosynthesis takes place over 8 10 weeks, from shortly after berry softening until harvest.

F3Hs are expressed at com parable levels in both anthocyanin pigmented and green skinned varieties, before and after the onset of ripening. However, regulation of F35Hs is largely genotype specific and responsive to environmental cues. The breadth of diversity in fruit colour among dif ferent grapevine accessions suggests a fine regulation of Drug_discovery F35H expression. Dark blue cultivars transcribe F35Hs at higher levels than light red cultivars, which neverthe less maintain traces of 35 OH anthocyanins and barely detectable F35H transcripts. In green skinned cultivars, F35H transcripts are completely absent.

In this connection, these authors showed that the process of HSC activation is accompanied by remarkable changes blog post in the expression of some key proteins involved in the control of apoptosis, and in particular, a shift towards a higher Bcl2/ Bax ratio protein expression. Based on this initial report, the aim of the present study was to further characterise the pathways modulating the apoptotic process in activated human HSCs. In order to maximise this effort, the expression and regulation of dif ferent cytoplasmic and nuclear protein systems were eval uated before and following stimulation with IGF I, a factor known to support growth, metabolism, differentia tion and prevention of apoptosis in many cell types. Although IGF I is produced by many tissues, liver IGF I synthesis accounts for 90% of the circulating peptide.

In particular, liver IGF I is synthesised at high levels in hepa tocytes in response to growth hormone stimulation, and in multiple non parenchymal cell types including HSC. These cells express IGF I receptor and are important targets for IGF I action. In cultured HSCs, IGF I enhances proliferation, migration and collagen synthesis, providing indirect evidence that IGF I could play a role in the expansion of activated HSCs and liver fibrosis. In previous studies, we investigated the intracellular pathway of human HSCs involved in both the mitogenic and chemotactic effects. In particular, it was shown that the activation of PI 3K and ERK is required for both IGF I dependent HSC proliferation and chemotaxis, confirm ing an interaction between PI 3K/Akt and MAPK/ERK pathways.

The aim of this study was to investigate Brefeldin_A the intracellular survival signal induced by IGF I and its pos sible biological effect. Materials and methods Materials Enhanced chemiluminescence reagents and nitro cellulose membrane Hybond C extra were from Amer sham Pharmacia Biotech,IMMOBILON Western reagents were from the Mil lipore Corporation IGF I and platelet derived growth factor from Peprotech EC Ltd, Fas ligand from Upstate Biotech. Antibody against Bad, Akt and poly polymerase were from Santa Cruz Biotechnology, all other antibodies were from Cell Signaling Tech nology. Iscoves medium was from Invitrogen. Annexin V FLUOS stain ing kit was from Roche. All other reagents were from Sigma Chemical Co.

Cell isolation and culture The use of human material was approved by the Human Research Review Committee of the University of Florence, where apply for it cells were isolated and characterised from surgical wedge sections of human livers not suitable for transplan tation, as described elsewhere. Cells obtained from samples of different normal human livers were cultured in Iscoves medium supplemented with 20% foetal bovine serum. After reaching confluence in the primary culture, serial passages were obtained, always applying a 1 3 split ratio.

The SOCS1 overe pressing HACs were cultured in pellets 24 hours before the stimulation with IL 1B. Overe pression and knockdown of human SOCS1 To generate the www.selleckchem.com/products/U0126.html pBABE viral vector containing the myc tagged human SOCS1, SOCS1 cDNA was amplified with two primer sets that con tained a BamH1 or EcoRI restriction enzyme site. PCR products were digested with BamH1 and EcoRI and cloned into the pBABE viral vectors. To produce retrovirus, the pBABE SOCS1 viral vectors were trans fected into a Platinum A retroviral packing cell line. Su pernatants were collected 72 hours after transfection. To infect SW1353 cells, viral supernatant was mi ed with fresh medium with 8 ug ml of polybrene at 1 1 ratio, and the mi ture was applied to freshly seeded cells.

To deliver SOCS1 or control shRNA into the SW1353 cells, SOCS1 shRNA or copGFP lentiviral particles were mi ed with fresh medium and 5 ug ml of polybrene, and the mi ture was applied to freshly seeded cells. Stable overe pressing or knockdown cell lines were selected with puromycin. To establish SOCS1 overe pressing HACs, pShuttle2 SOCS1 or empty vector was electro transfected by using a Gene Pulser cell System under the condition of 50 V and 2 ms pulse. Measurement of MMPs and TIMP 1 in culture supernatants Nontransfected and transfected SW1353 cells were plated onto 48 well plates for 24 hours and then pretreated with serum free media for 2 hours. The cells were stimulated with IL 1B for 24 hours. The concentrations of MMP 1, 3, and ?13 and TIMP 1 in the conditioned media were measured with commercial ELISA kits according to the manufac turers instructions.

Reverse transcriptase polymerase chain reaction for SOCS 1 Quantitative real time RT PCR was performed by using an ABI 7500 real time PCR machine. Specific Taqman primers and probes for SOCS1 MMP 1 MMP 3, MMP 13, ADAMTS4 were purchased from Applied Biosystems. AV-951 The number fold difference in the e pression of tar get mRNA was calculated with a comparative Ct method, normalized to GAPDH. Western blotting and immunoprecipitation To prepare the total cell lysates, SW1353 cells were washed twice with ice cold PBS, harvested, and lysed in IP buffer, 150 mM NaCl, 1% Triton 100, 25 mM B glycerophosphate, phosphatase inhibitor cocktail, and protease inhibitor cocktail for 60 minutes on ice. For immunoprecipitation, TAK1 antibody was added to the whole cell e tracts and incubated on a rotator overnight at 4 C.

Then the protein G agarose beads choose size were further incu bated for 3 hours at 4 C. The mi tures were centri fuged at 2,095 g for 3 minutes. The precipitates were washed 3 times by using pre cold IP buffer, and the beads were resuspended in 2�� SDS sample buffer. The immunoprecipitates or the whole cell lysates were separated on 10% denaturing polyacrylamide gels and transferred to polyvinylidene difluoride membranes.

Human cell culture, treatments, imaging and cell cycle analysis The HeLa cell and MCF 7 cell lines were purchased from ATCC. http://www.selleckchem.com/products/Pazopanib-Hydrochloride.html HeLa cells were grown in MEM supple mented with 10% foetal calf serum, 2 mM L glu tamine, penicillin, streptomycin and non essential amino acids, at 37 C in 5% CO2. Media, serum and reagents for tissue culture were purchased from GIBCO . MCF 7 cells were grown in MEM supplemented with 10% FCS, non essential amino acids, 1 mg/100 ml insulin, 8. 4 mg/100 ml NaHCO3 at 37 C in 5% CO2. HT/HCA Image analysis typically 5000 HeLa and 10000 MCF 7 cells were seeded in 96 well Greiner Bio One plates and left to attach overnight in their respec tive media. The indicated amounts of FTI 277 or the vehicle were added and the cells were grown for a further 48 hours.

Cells were then washed in 1�� phosphate buffered saline and fixed for 10 min with 4% paraformaldehyde in 1 PBS, and permeabi lized for 30 min in blocking buffer. Nuclei were stained with Hoechst, washed three times and inspected using a 20�� objective of the ScanR imaging platform . Sixteen images were acquired randomly per well. For cell cycle analysis at least three wells per con dition were considered for statistical analysis of the HeLa and MCF 7 cells. For all the others five wells were considered. Determination of mitotic cell number fixed cells were incubated for 75 min with a PhosphoH3 pSer10 diluted 1 100 in blocking buffer, washed three times in 1 PBS, and further incubated for 30 min with anti mouse Alexa488 conjugates diluted 1 500 in blocking buffer, washed three times and inspected using the ScanR microscope.

For determination of Pak1/2/3 localization, Cilengitide an anti Pak C19 antibody and anti rabbit Alexa546 were used. For determination of Aurora A localization, an anti IAK1 and anti mouse Alexa488 conju gates were used. HeLa cells were treated for 48 hours with 2 uM of FTI 277 or with the vehicle, and then fixed using the procedure indicated above. To determine the phosphorylation of ribosomal pro tein S6, an Alexa555 conjugated anti PhosphoS6 anti body was used. Typically 4000 HeLa and 8000 MCF 7 cells were seeded in five wells per experimental condition. Cells were left to attach over night, and treated with 5 uM of FTI 277 or with the vehicle for 24 hours in starvation medium. Cells were fixed, washed and probed with Hoechst and processed for ScanR acquisition as described above.

Quantification and statistical analysis were per formed with the in built ScanR analysis software. Introduction Although significant advances have been made in selleck chem the treat ment of acute lymphoblastic leukemia especially in children, only 30 40% of adults have a long term survival. A major subclass of ALL with a specially poor progno sis in both adults and children is that of Philadelphia chromosome positive ALL. The Ph chromosome is generated by a reciprocal t translocation. It is found in around 30% of cases of adult ALL and is the hallmark of chronic myeloid leukemia.