8 research outputs found
In Vitro Transformation of Primary Human CD34+ Cells by AML Fusion Oncogenes: Early Gene Expression Profiling Reveals Possible Drug Target in AML
Different fusion oncogenes in acute myeloid leukemia (AML) have distinct clinical and laboratory features suggesting different modes of malignant transformation. Here we compare the in vitro effects of representatives of 4 major groups of AML fusion oncogenes on primary human CD34+ cells. As expected from their clinical similarities, MLL-AF9 and NUP98-HOXA9 had very similar effects in vitro. They both caused erythroid hyperplasia and a clear block in erythroid and myeloid maturation. On the other hand, AML1-ETO and PML-RARA had only modest effects on myeloid and erythroid differentiation. All oncogenes except PML-RARA caused a dramatic increase in long-term proliferation and self-renewal. Gene expression profiling revealed two distinct temporal patterns of gene deregulation. Gene deregulation by MLL-AF9 and NUP98-HOXA9 peaked 3 days after transduction. In contrast, the vast majority of gene deregulation by AML1-ETO and PML-RARA occurred within 6 hours, followed by a dramatic drop in the numbers of deregulated genes. Interestingly, the p53 inhibitor MDM2 was upregulated by AML1-ETO at 6 hours. Nutlin-3, an inhibitor of the interaction between MDM2 and p53, specifically inhibited the proliferation and self-renewal of primary human CD34+ cells transduced with AML1-ETO, suggesting that MDM2 upregulation plays a role in cell transformation by AML1-ETO. These data show that differences among AML fusion oncogenes can be recapitulated in vitro using primary human CD34+ cells and that early gene expression profiling in these cells can reveal potential drug targets in AML
Dissection of the Transformation of Primary Human Hematopoietic Cells by the Oncogene NUP98-HOXA9
NUP98-HOXA9 is the prototype of a group of oncoproteins associated with acute myeloid leukemia. It consists of an N-terminal portion of NUP98 fused to the homeodomain of HOXA9 and is believed to act as an aberrant transcription factor that binds DNA through the homeodomain. Here we show that NUP98-HOXA9 can regulate transcription without binding to DNA. In order to determine the relative contributions of the NUP98 and HOXA9 portions to the transforming ability of NUP98-HOXA9, the effects of NUP98-HOXA9 on primary human CD34+ cells were dissected and compared to those of wild-type HOXA9. In contrast to previous findings in mouse cells, HOXA9 had only mild effects on the differentiation and proliferation of primary human hematopoietic cells. The ability of NUP98-HOXA9 to disrupt the differentiation of primary human CD34+ cells was found to depend primarily on the NUP98 portion, whereas induction of long-term proliferation required both the NUP98 moiety and an intact homeodomain. Using oligonucleotide microarrays in primary human CD34+ cells, a group of genes was identified whose dysregulation by NUP98-HOXA9 is attributable primarily to the NUP98 portion. These include RAP1A, HEY1, and PTGS2 (COX-2). Their functions may reflect the contribution of the NUP98 moiety of NUP98-HOXA9 to leukemic transformation. Taken together, these results suggest that the effects of NUP98-HOXA9 on gene transcription and cell transformation are mediated by at least two distinct mechanisms: one that involves promoter binding through the homeodomain with direct transcriptional activation, and another that depends predominantly on the NUP98 moiety and does not involve direct DNA binding
Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries
Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely
Influence of Seed Soaking and Foliar Application Using Ozonated Water on Two Sweet Pepper Hybrids under Cold Stress
The harmful impacts of ozone (O3) on plant development and productivity have been excessively studied. Furthermore, the positive influences of its low concentrations still need to be explored further. The present study was performed to assess the impact of low concentrations of O3 on two sweet pepper hybrids under cold stress. The ozonated water was utilized for seed soaking or foliar application at concentrations of 0, 10, 20, 30, and 40 ppm. Seed soaking using ozonated water for 1 h was compared to soaking in distilled water as a control. Moreover, exogenously ozonated water was sprayed thrice at three-day intervals compared with untreated control. The differences between the applied methods (seed soaking and foliar application using ozonated water) were not statistically detected in most of the evaluated parameters. On the other hand, the evaluated hybrids displayed significant differences in the studied parameters, with the superiority of the Lirica evident in most germination and seedling growth parameters. Both applied methods significantly improved germination and seedling growth parameters. In particular, the concentration of 40 ppm displayed the highest enhancement of the germination index, coefficient velocity, and seedling quality. In addition, it promoted the seedling maintenance of high relative water content (RWC), chlorophyll, proline, and ascorbate peroxidase activity under cold stress conditions. Moreover, it protected the cell wall from damage by decreasing membrane permeability (MP). Generally, the best results were obtained from 40 ppm followed by 30 ppm of O3 as seed soaking or foliar spray. The results pointed out the possible use of O3 in a low concentration to protect the plants from cold stress during germination and early plant growth
Influence of Seed Soaking and Foliar Application Using Ozonated Water on Two Sweet Pepper Hybrids under Cold Stress
The harmful impacts of ozone (O3) on plant development and productivity have been excessively studied. Furthermore, the positive influences of its low concentrations still need to be explored further. The present study was performed to assess the impact of low concentrations of O3 on two sweet pepper hybrids under cold stress. The ozonated water was utilized for seed soaking or foliar application at concentrations of 0, 10, 20, 30, and 40 ppm. Seed soaking using ozonated water for 1 h was compared to soaking in distilled water as a control. Moreover, exogenously ozonated water was sprayed thrice at three-day intervals compared with untreated control. The differences between the applied methods (seed soaking and foliar application using ozonated water) were not statistically detected in most of the evaluated parameters. On the other hand, the evaluated hybrids displayed significant differences in the studied parameters, with the superiority of the Lirica evident in most germination and seedling growth parameters. Both applied methods significantly improved germination and seedling growth parameters. In particular, the concentration of 40 ppm displayed the highest enhancement of the germination index, coefficient velocity, and seedling quality. In addition, it promoted the seedling maintenance of high relative water content (RWC), chlorophyll, proline, and ascorbate peroxidase activity under cold stress conditions. Moreover, it protected the cell wall from damage by decreasing membrane permeability (MP). Generally, the best results were obtained from 40 ppm followed by 30 ppm of O3 as seed soaking or foliar spray. The results pointed out the possible use of O3 in a low concentration to protect the plants from cold stress during germination and early plant growth
Organoboronic acids/esters as effective drug and prodrug candidates in cancer treatments: challenge and hope
AbstractBoronic acids/esters have recently emerged in the field of medicinal and pharmaceutical research due to their exceptional oxophilicity, low toxicity, and unique structure. They are known as potent enzyme inhibitors, cancer therapy capture agents, and can mimic certain types of antibodies to fight infections. They have been designed and developed into drugs, and this approach has emerged in the last 20 years. Five boronic acid drugs have been approved by the FDA and Health Canada, two of which are used to treat cancer, specifically multiple myeloma. The purpose of this review is to investigate boronic acid/ester derivatives as potential pharmaceutical agents as well as the mechanism of action. It will concentrate on six types of cancer: multiple myeloma, prostate cancer, breast cancer, lung cancer, cervical cancer, and colon cancer. Some newly developed boron-containing compounds have already demonstrated highly promising activities, but further investigation is required before final conclusions can be drawn