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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The first definitive long-term repopulating hematopoietic stem cells (HSCs) emerge from and undergo rapid expansion in the embryonic aorta-gonad-mesonephros (AGM) region. To investigate the presumptive unique characteristics of the embryonic hematopoietic microenvironment and its surrounding tissues, we have generated stromal clones from subdissected day 10 and day 11 AGMs, embryonic livers (ELs) and gut mesentery. We here examine the ability of 19 of these clones to sustain extended long-term cultures (LTCs) of human CD34(+) umbilical cord blood (UCB) cells in vitro. The presence of in vitro repopulating cells was assessed by sustained production of progenitor cells (extended LTC-CFC) and cobblestone area-forming cells (CAFC). The embryonic stromal clones differed greatly in their support for human HSCs. Out of eight clones tested in the absence of exogenous cytokines, only one (EL-derived) clone was able to provide maintenance of HSCs. Addition of either Tpo or Flt3-L + Tpo improved the long-term support of about 50% of the tested clones. Cultures on four out of 19 clones, ie the EL-derived clone mentioned, two urogenital-ridge (UG)-derived clones and one gastrointestinal (GI)-derived clone, allowed a continuous expansion of primitive CAFC and CFU-GM with over several hundred-fold more CAFC(week6) produced in the 12th week of culture. This expansion was considerably higher than that found with the FBMD-1 cell line, which is appreciated by many investigators for its support of human HSCs, under comparable conditions. This stromal cell panel derived from the embryonic regions may be a powerful tool in dissecting the factors mediating stromal support for maintenance and expansion of HSCs.
Leukemia 2002 Sep
PMID:Stromal cells from murine embryonic aorta-gonad-mesonephros region, liver and gut mesentery expand human umbilical cord blood-derived CAFC(week6) in extended long-term cultures. 1220 Jun 94

Emodin is a naturally occurring anthraquinone present in the roots and bark of numerous plants of the genus Rhamnus. Extracts from the roots, bark, and/or dried leaves of buckthorn, senna, cascara, aloe, frangula, and rhubarb have been used as laxatives since ancient times and currently are widely used in the preparation of herbal laxative preparations. Anthraquinone glycosides are poorly absorbed from the gastrointestinal tract but are cleaved by gut bacteria to produce aglycones (such as emodin) that are more readily absorbed and are responsible for the purgative properties of these preparations. There is extensive exposure to emodin and other anthraquinones resulting from the use of herb-based stimulant laxatives. Reports that 1,8-dihydroxyanthraquinone, a commonly used laxative ingredient, caused tumors in the gastrointestinal tract of rats raised the possibility of an association between colorectal cancer and the use of laxatives containing anthraquinones. Because emodin is a hydroxyanthraquinone structurally similar to 1,8-dihydroxyanthraquinone, is present in herbal laxatives, and was reported to be mutagenic in bacteria, it was considered a potential carcinogen and was selected for in-depth evaluation. Male and female F344/N rats and B6C3F1 mice were exposed to emodin (at least 94% pure) in feed for 16 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, rat and mouse bone marrow cells, and mouse peripheral blood erythrocytes. 16-DAY STUDY IN RATS: Groups of five male and five female rats were fed diets containing 0, 600, 2,000, 5,500, 17,000, or 50,000 ppm emodin (equivalent to average daily doses of approximately 50, 170, 480, 1,400, or 3,700 mg emodin/kg body weight to males and 50, 160, 460, 1,250, or 2,000 mg/kg to females) for 15 (males) or 16 (females) days. Three female rats died before the end of the study. Mean body weights of males and females exposed to 5,500 ppm or greater were significantly less than those of the controls. Feed consumption by males and females receiving 17,000 or 50,000 ppm was decreased throughout the study. Macroscopic lesions were present in the kidney of rats exposed to 17,000 or 50,000 ppm. 16-DAY STUDY IN MICE: Groups of five male and five female mice were fed diets containing 0, 600, 2,000, 5,500, 17,000, or 50,000 ppm emodin (equivalent to average daily doses of approximately 120, 400, 1,200, or 3,800 mg/kg to males and 140, 530, 1,600, or 5,000 mg/kg to females; 50,000 ppm equivalents were not calculated due to high mortality) for 15 (males) or 16 (females) days. All mice exposed to 50,000 ppm died before the end of the study. Mice in the 17,000 ppm groups lost weight during the study. Feed consumption by 5,500 ppm females was greater than that by the controls throughout the study. Macroscopic lesions were present in the gallbladder and kidney of mice exposed to 17,000 ppm. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 312.5, 625, 1,250, 2,500, or 5,000 ppm emodin (equivalent to average daily doses of approximately 20, 40, 80, 170, or 300 mg/kg to males and females) for 14 weeks. Mean body weights of males exposed to 2,500 ppm or greater and females exposed to 1,250 ppm or greater were significantly less than those of the controls. During the first week of the study, feed consumption by males exposed to 2,500 or 5,000 ppm and females exposed to 5,000 ppm was less than that by the controls. Feed consumption by these groups was similar to that by the controls for the remainder of the study. In rats exposed to 2,500 or 5,000 ppm, there were increases in platelet counts in males and females and segmented neutrophil counts in females. Total serum protein and albumin concentrations were decreased in females exposed to 2,500 or 5,000 ppm. Relative kidney weights of rats exposed to 1,250 ppm or greater and relative lung weights of rats exposed to 625 ppm or greater were significantly increased compared to the control groups. Relative liver weights were incree increased in females exposed to 625 ppm or greater. The estrous cycle length wassignificantly increased in females exposed to 1,250 or 5,000 ppm. All male rats exposed to 1,250 ppm or greater and all exposed female rats had pigment in the renal tubules; and the severity of pigmentation generally increased with increasing exposure concentration. The incidences of hyaline droplets in the cortical epithelial cytoplasm were increased in all groups of exposed males and in females exposed to 312.5, 625, or 1,250 ppm. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were fed diets containing 0, 312.5, 625, 1,250, 2,500, or 5,000 ppm emodin (equivalent to average daily doses of approxi mately 50, 100, 190, 400, or 800 mg/kg to males and 60, 130, 240, 500, or 1,100 mg/kg to females) for 14 weeks. All mice survived to the end of the study. Mean body weights of males exposed to 2,500 or 5,000 ppm were significantly less than those of the controls. Feed consumption by exposed groups was generally similar to that by the controls. Relative kidney weights of male mice exposed to 1,250 ppm or greater, relative lung weights of males exposed to 625 ppm or greater, and relative liver weights of female mice exposed to 625 ppm or greater were increased. The incidences and severities of nephropathy were increased in males and females exposed to 1,250 ppm or greater. The incidences of renal tubule pigmentation were significantly increased in males exposed to 625 ppm or greater and in females exposed to 1,250 ppm or greater. 2-YEAR STUDY IN RATS: Groups of 65 male and 65 female rats were fed diets containing 0, 280, 830, or 2,500 ppm emodin (equivalent to average daily doses of approximately 110, 320, or 1,000 mg/kg to males and 120, 370, or 1,100 mg/kg to females) for 105 weeks. Ten male and ten female rats from each group were necropsied at 6 months. Blood samples from five male and five female rats in each group were evaluated at 3, 6, and 12 months for plasma emodin concentrations; these rats were necropsied at 12 months. Survival, Body Weights, and Feed Consumption: Survival of exposed males and females was similar to that of the controls. The mean body weights of rats in the 2,500 ppm groups were less than those of the controls beginning at week 2 of the study. Feed consumption by exposed groups was similar to that by the controls throughout the study. Pathology Findings: Three Zymbal's gland carcinomas were observed in female rats exposed to 2,500 ppm. This incidence exceeded the range observed for current historical controls and was considered an equivocal finding. At the 6- and 12-month interim evaluations and at 2 years, emodin-related increases in the incidences of renal tubule hyaline droplets occurred in all exposed groups. The incidences of renal tubule pigmentation were significantly increased in all exposed groups of males at 2 years. There were negative trends in the incidences of mononuclear cell leukemia in male and female rats, and the incidences in the 2,500 ppm groups were significantly decreased. In females exposed to 2,500 ppm, the incidence was below the historical control range; the incidence in males exposed to 2,500 ppm was at the lower end of the historical control range. 2-YEAR STUDY IN MICE: Groups of 60 male mice were fed diets containing 0, 160, 312, or 625 ppm emodin (equivalent to average daily doses of approximately 15, 35, or 70 mg/kg) for 105 weeks. Groups of 60 female mice were fed diets containing 0, 312, 625, or 1,250 ppm emodin (equivalent to average daily doses of approximately 30, 60, or 120 mg/kg) for 105 weeks. Ten male and ten female mice from each group were necropsied at 12 months. Survival, Body Weights, and Feed Consumption Survival and mean body weights of exposed males and females were similar to those of the controls. No differences in feed consumption were noted between exposed and control groups. Pathology Findings: Low incidences of renal tubule adenoma and carcinoma occurred in exposed male mice; these incidences included one carcinoma each in the 312 and 625 ppm groups. Renal tubule neoplasms are rare in male mice, and their presence in these groups suggested a possible association with emodin exposure. At the 12-month interim evaluation, the severity of nephropathy was slightly increased in males exposed to 625 ppm. Also at 12 months, the severity of nephropathy increased from minimal in the lower exposure groups to mild in females exposed to 1,250 ppm; the incidence in this group was significantly increased compared to the control group. At 2 years, the severities of nephropathy were slightly increased in males exposed to 625 ppm and females exposed to 1,250 ppm. The incidences of nephropathy were significantly increased in all exposed groups of females. At the 12-month interim evaluation, the incidences of renal tubule pigmentation were significantly increased in all exposed groups of males and in females exposed to 625 or 1,250 ppm. The severities increased with increasing exposure concentration. At 2 years, the incidences of renal tubule pigmentation were significantly increased in all exposed groups; severities increased with increasing exposure concentration. GENETIC TOXICOLOGY: Emodin was mutagenic in Salmonella typhimurium strain TA100 in the presence of S9 activation; no mutagenicity was detected in strain TA98, with or without S9. Chromosomal aberrations were induced in cultured Chinese hamster ovary cells treated with emodin, with and without S9. Three separate in vivo micronucleus tests were performed with emodin. A male rat bone marrow micronucleus test, with emodin administered by three intraperitoneal injections, gave negative results. Results of acute-exposure (intraperitoneal injection) micronucleus tests in bone marrow and peripheral blood erythrocytes of male and female mice were negative. In a peripheral blood micronucleus test on mice from the 14-week study, negative results were seen in male mice, but a weakly positive response was observed in similarly exposed females. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of emodin in male F344/N rats exposed to 280, 830, or 2,500 ppm. There was equivocal evidence of carcinogenic activity of emodin in female F344/N rats based on a marginal increase in the incidence of Zymbal's gland carcinoma. There was equivocal evidence of carcinogenic activity of emodin in male B6C3F1 mice based on a low incidence of uncommon renal tubule neoplasms. There was no evidence of carcinogenic activity of emodin in female B6C3F1 mice exposed to 312, 625, or 1,250 ppm. Exposure of rats to emodin resulted in increased incidences of renal tubule hyaline droplets and pigmentation in males, increased incidences of renal tubule hyaline droplets in females, and increased severities of renal tubule pigmentation in males and females. Emodin exposure resulted in increased incidences of renal tubule pigmentation in male and female mice and increased incidences of nephropathy in female mice. Incidences of mononuclear cell leukemia decreased in male and female rats exposed to 2,500 ppm. Synonyms: Archin; C.I. 75440; C.I. Natural Green 2; C.I. Natural Yellow 14; emodol; frangulic acid; frangula emodin; 6-methyl- 1,3,8-trihydroxyanthraquinone; Persian Berry Lake; rheum emodin; schuttgelb; 1,3,8-trihydroxy-6-methyl-9,10- anthracenedione; 1,3,8-trihydroxy-6-methylanthraquinone; 4,5,7-trihydroxy-2-methylanthraquinone.
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PMID:NTP Toxicology and Carcinogenesis Studies of EMODIN (CAS NO. 518-82-1) Feed Studies in F344/N Rats and B6C3F1 Mice. 1256 47

YNK01 (Starasid) is a prodrug that is adsorbed in the gut and is transformed in the liver in arabinosyl cytosine (AC). Low-dose AC (LDAC) is useful for the treatment of Philadelphia positive (Ph+) chronic myeloid leukemia (CML), especially in combination with alpha-interferon (alphaIFN). The use of YNK01 can avoid the daily s.c. injection of conventional AC. To assess the safety and the efficacy of alphaIFN and YNK01, we enrolled 86 consecutive previously untreated chronic phase Ph+ CML patients in a phase II study of alphaIFN (Intron-A) 5 MIU/m(2) daily and YNK01 600 mg daily 14 days a month. The 6-month complete hematologic response and the 12-month major cytogenetic response rates were 78 and 28%, respectively. In a prior study of alphaIFN and conventional LDAC, they were 62 and 22%, respectively. However, the compliance to the treatment was poor, with 25% of cases discontinuing the treatment within the first year. This was not because of the severity of the side effects but because of the frequency, duration and repetition of the side effects, for an overall frequency of 13.17 adverse events, mostly grade 1 and 2, per patient per year. Therefore, the study of this effective combination is being pursued, testing lower doses of alphaIFN and YNK01.
Leukemia 2003 Mar
PMID:A phase II study of alpha-interferon and oral arabinosyl cytosine (YNK01) in chronic myeloid leukemia. 1264 44

Allogeneic stem cell transplantation (SCT) is an important therapy for a number of malignant diseases, and acute graft versus host disease (GVHD) and leukemic relapse remain the two major obstacles to successful outcomes of this treatment strategy. The therapeutic potential of allogeneic SCT relies on the graft versus leukemia (GVL) effect, during which donor T lymphocytes eradicate residual malignant cells via immunological mechanisms. Unfortunately, beneficial GVL effects are closely associated with the toxicity of GVHD. The pathophysiology of GVHD is complex and fundamentally depends upon aspects of adaptive immunity and interactions between donor T cells and foreign host tissue antigens. Recent work has revealed that components of the innate immune response and the secretion of inflammatory cytokine effectors are also important. In this context, experimental studies have demonstrated that loss of gastrointestinal (GI) tract integrity plays a major role in the amplification of systemic GVHD. Specifically, translocation of endotoxin across a damaged GI tract and into the circulation promotes local and systemic cytokine release. This effect perpetuates further gut mucosal injury and endotoxin leak, thus establishing a positive feedback loop for progressive target organ injury and systemic inflammation. Data obtained using murine SCT models have shown that disruption of the cellular activating effects of lipopolysaccharide (LPS) significantly reduces cytokine secretion and GVHD severity without altering T-cell responses to host antigens. These findings support a critical role for LPS in the early inflammatory events responsible for GVHD and suggest that strategies which target the innate immune response and LPS receptor-ligand interactions may help prevent GVHD while preserving donor T-cell responses and GVL activity.
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PMID:The role of endotoxin and the innate immune response in the pathophysiology of acute graft versus host disease. 1269 87

Telomerase activity and telomere maintenance have been associated with immortality in tumor and embryonic stem cells. Whereas most normal somatic cells are telomerase negative, low levels of this enzyme have been found in adult stem cells from the skin, gut and the hematopoietic system. Here, we show that telomerase activity is not detectable in human mesenchymal stem cells (hMSCs), which have the phenotype SH2+, SH3+, SH4+, CD29+, CD44+, CD14-, CD34- and CD45-, and have the capacity to differentiate into adipocytes, chondrocytes and osteoblasts. These data suggest that hMSCs have a different telomere biology compared to other adult stem cells. Alternatively, true mesenchymal stem cells might be a very rare subpopulation that have a detection level that is below the sensitivity of the TRAP assay.
Leukemia 2003 Jun
PMID:Lack of telomerase activity in human mesenchymal stem cells. 1276 82

Five patients with confirmed Fanconi's anemia (FA) and myelodysplasia and/or leukemia underwent stem cell transplantation (SCT) from related donors at KFSHRC. The median age at SCT was 12.6 year (range, 6.2-15 years). Conditioning regimen consisted of cyclophosphamide (CY) 5 mg/kg/day i.v. for 4 days, total body irradiation (TBI) 450 cGy in a single dose. Graft-versus-host disease (GVHD) prophylaxis was with cyclosporine and antithymocyte globulins (ATG). The median time to engraftment (defined as ANC>/=0.5 x 10(9)/l) was 16 days (range, 12-26 days). The median time to a self-sustaining platelet count of >/=20 x 10(9)/l was 27 days (range, 12-40 days). All patients engrafted. Two patients developed acute GVHD; one of the gut (grade 3) and the other of the skin (grade 1), and one patient developed chronic GVHD of the liver. Four are alive and well with no evidence of the disease; one patient died of bacterial sepsis after controlling her GVHD and clearing her pulmonary aspergillosis and CMV infection. We conclude that the use of low-dose CY plus TBI in patients with FA and MDS/AML undergoing SCT is adequate; the regimen is well tolerated and may be curative for such patients.
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PMID:Allogeneic stem cell transplantation in patients with Fanconi's anemia and myelodysplasia or leukemia utilizing low-dose cyclophosphamide and total body irradiation. 1457 32

We report a 10-year-old male with Down's syndrome, who received a bone marrow transplant for acute lymphoblastic leukaemia. Subsequent acute graft-versus-host disease (GvHD) of the gut progressed to small bowel obstruction. At laparotomy, the small bowel appeared solid and contracted with no or minimal luminal patency. Although the caecum had a lumen, it was indistensible, and it was not possible to enter the terminal ileum. Histology of the obstructed bowel showed extensive necrosis of the mucosa, muscularis mucosa and submucosa of most of the small bowel wall, causing obliteration of the lumen. The changes were presumed to be related to post inflammatory atrophy. This extreme manifestation of GvHD could thus be called obliterative enteritis. Both cytomegalovirus and adenovirus were isolated from the patient. These viruses may have contributed to the severity of the intestinal GvHD.
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PMID:Obliterative enteritis complicating graft versus host disease. 1462 82

In this study, we identified 53 aberrantly hypermethylated DNA sequences in adult T-cell leukemia (ATL) cells using methylated CpG island amplification/representational difference analysis method. We also observed a proportionate increase in the methylation density of these regions with disease progression. Seven genes, which were expressed in normal T cells, but suppressed in ATL cells, were identified near the hypermethylated regions. Among these silenced genes, Kruppel-like factor 4 (KLF4) gene is a cell cycle regulator and early growth response 3 (EGR3) gene is a critical transcriptional factor for induction of Fas ligand (FasL) expression. Treatment with 5-aza-2'-deoxycytidine resulted in the recovery of their transcription, indicating that their silencing might be associated with DNA hypermethylation. To study their functions in ATL cells, we transfected recombinant adenovirus vectors expressing KLF4 and EGR3 genes. Expression of KLF4 induced apoptosis of ATL cells whereas enforced expression of EGR3 induced the expression of FasL gene, resulting in apoptosis. Thus, suppressed expression of EGR3 enabled ATL cells to escape from activation-induced cell death mediated by FasL. Our results showed that the methylated CpG island amplification/representational difference analysis method allowed the isolation of hypermethylated DNA regions specific to leukemic cells and thus shed light on the roles of DNA methylation in leukemogenesis.
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PMID:Identification of aberrantly methylated genes in association with adult T-cell leukemia. 1534 80

With the recent progress in reduced-intensity conditioning stem cell transplantation (RIST) and taking into consideration the concept of feto-maternal immunological tolerance, we carried out non-T-cell depleted HLA haploidentical RIST from noninherited maternal antigen (NIMA) complementary siblings or offspring donors for four older patients: a patient with myeloplastic syndrome (MDS) and three patients with adult T-cell leukemia (ATL) in partial remission or with progressive disease. All patients showed early, durable engraftment, and no serious toxicities were observed apart from grade III mucositis in one case. Grade II acute GVHD occurred in two cases, which was well-controlled. In one ATL patient whose donor did not have NIMA microchimerism, tacrolimus could not be continued after engraftment due to renal dysfunction, and grade III acute GVHD (gut: stage 4) occurred on day 35. A patient with MDS was free from disease (requiring no transfusions and with a normal bone marrow) for 15 months. Two cases of ATL relapsed. Feto-maternal tolerance may lead to new RIST strategies in the haploidentical reduced-intensity situation, but further evaluation is required.
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PMID:Reduced-intensity non-T-cell depleted HLA-haploidentical stem cell transplantation for older patients based on the concept of feto-maternal tolerance. 1536 2

Intestinal cholesterol absorption is an important regulator of serum cholesterol levels. Ezetimibe is a specific inhibitor of intestinal cholesterol absorption recently introduced into medical practice; its mechanism of action, however, is still unknown. Ezetimibe neither influences the release of cholesterol from mixed micelles in the gut lumen nor the transfer of cholesterol to the enterocyte brush border membrane. With membrane-impermeable Ezetimibe analogues we could demonstrate that binding of cholesterol absorption inhibitors to the brush border membrane of small intestinal enterocytes from the gut lumen is sufficient for inhibition of cholesterol absorption. A 145-kDa integral membrane protein was identified as the molecular target for cholesterol absorption inhibitors in the enterocyte brush border membrane by photoaffinity labeling with photoreactive Ezetimibe analogues (Kramer, W., Glombik, H., Petry, S., Heuer, H., Schafer, H. L., Wendler, W., Corsiero, D., Girbig, F., and Weyland, C. (2000) FEBS Lett. 487, 293-297). The 145-kDa Ezetimibe-binding protein was purified by three different methods and sequencing revealed its identity with the membrane-bound ectoenzyme aminopeptidase N ((alanyl)aminopeptidase; EC 3.4.11.2; APN; leukemia antigen CD13). The enzymatic activity of APN was not influenced by Ezetimibe (analogues). The uptake of cholesterol delivered by mixed micelles by confluent CaCo-2 cells was partially inhibited by Ezetimibe and nonabsorbable Ezetimibe analogues. Preincubation of confluent CaCo-2 cells with Ezetimibe led to a strong decrease of fluorescent APN staining with a monoclonal antibody in the plasma membrane. Independent on its enzymatic activity, aminopeptidase N is involved in endocytotic processes like the uptake of viruses. Our findings suggest that binding of Ezetimibe to APN from the lumen of the small intestine blocks endocytosis of cholesterol-rich membrane microdomains, thereby limiting intestinal cholesterol absorption.
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PMID:Aminopeptidase N (CD13) is a molecular target of the cholesterol absorption inhibitor ezetimibe in the enterocyte brush border membrane. 1549 15


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