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Blood Advances Nov 2022Autologous stem cell transplant with gene therapy (ASCT-GT) provides curative therapy while reducing pretransplant immune-suppressive conditioning and eliminating... (Clinical Trial)
Clinical Trial
Autologous stem cell transplant with gene therapy (ASCT-GT) provides curative therapy while reducing pretransplant immune-suppressive conditioning and eliminating posttransplant immune suppression. Clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations increase and telomere lengths (TLs) shorten with natural aging and DNA damaging processes. It is possible that, if CHIP is present before ASCT-GT or mutagenesis occurs after busulfan exposure, the hematopoietic stem cells carrying these somatic variants may survive the conditioning chemotherapy and have a selective reconstitution advantage, increasing the risk of hematologic malignancy and overall mortality. Seventy-four peripheral blood samples (ranging from baseline to 120 months after ASCT-GT) from 10 pediatric participants who underwent ASCT-GT for adenosine deaminase-deficient severe combined immune deficiency (ADA-SCID) after reduced-intensity conditioning with busulfan and 16 healthy controls were analyzed for TL and CHIP. One participant had a significant decrease in TL. There were no CHIP-associated mutations identified by the next-generation sequencing in any of the ADA-SCID participants. This suggests that further studies are needed to determine the utility of germline analyses in revealing the underlying genetic risk of malignancy in participants who undergo gene therapy. Although these results are promising, larger scale studies are needed to corroborate the effect of ASCT-GT on TL and CHIP. This trial was registered at www.clinicaltrials.gov as #NCT00794508.
Topics: Child; Humans; Busulfan; Clonal Hematopoiesis; Genetic Therapy; Severe Combined Immunodeficiency
PubMed: 35914227
DOI: 10.1182/bloodadvances.2022007803 -
Cancer Medicine Aug 2023The present study aimed to examine the association between the conditioning intensity and height growth in pediatric patients who underwent allogeneic hematopoietic stem... (Review)
Review
BACKGROUND
The present study aimed to examine the association between the conditioning intensity and height growth in pediatric patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT).
METHODS
We reviewed the clinical records of 89 children with malignant diseases who underwent initial allo-HSCT between 2003 and 2021. Height measurements were standardized using standard height charts prepared by the Japanese Society for Pediatric Endocrinology to calculate standard deviation score (SDS). We defined short stature as a height SDS less than -2.0 in that reference. Myeloablative conditioning (MAC) comprised total-body irradiation at more than 8 Gy and busulfan administration at more than 8 mg/kg (more than 280 mg/m ). Other conditioning regimens were defined as reduced intensity conditioning (RIC).
RESULTS
A total of 58 patients underwent allo-HSCT with MAC, and 31 patients received allo-HSCT with RIC. There were significant differences in the height SDS at 2 and 3 years after allo-HSCT between MAC and RIC group (-1.33 ± 1.20 vs. -0.76 ± 1.12, p = 0.047, -1.55 ± 1.28 vs. -0.75 ± 1.11, p = 0.022, respectively). Multivariate logistic regression analysis with the adjustments for potential confounding factors of patients less than 10 years of age at allo-HSCT and chronic graft-versus host disease demonstrated that MAC regimen was associated with a markedly increased risk of a short stature at 3 years after allo-HSCT (adjusted odds ratio, 5.61; 95% confidence interval, 1.07-29.4; p = 0.041).
CONCLUSION
The intensity of conditioning regimen may be associated with short statures after allo-HSCT.
Topics: Humans; Child; Graft vs Host Disease; Transplantation, Homologous; Hematopoietic Stem Cell Transplantation; Busulfan; Bronchiolitis Obliterans Syndrome; Transplantation Conditioning; Retrospective Studies
PubMed: 37434385
DOI: 10.1002/cam4.6336 -
Ecotoxicology and Environmental Safety May 2021Perfluorooctane sulfonate is related to male reproductive dysfunction in rats and humans. However, the underlying mechanism remains unknown. Here, we reported the...
Perfluorooctane sulfonate is related to male reproductive dysfunction in rats and humans. However, the underlying mechanism remains unknown. Here, we reported the effects of short-term exposure to perfluorooctane sulfonate on the regeneration of Leydig cells in vivo and investigated possible mechanisms in vitro. After adult male Sprague-Dawley rats were gavaged perfluorooctane sulfonate (0, 5 or 10 mg/kg/day) for 7 days and then injected intraperitoneally ethane dimethane sulfonate next day to eliminate Leydig cells, the Leydig cell regeneration process was monitored. Perfluorooctane sulfonate significantly lowered serum testosterone levels, reduced the number of regenerated Leydig cells, down-regulated the expression of Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, Cyp17a1, and Dhh) and their proteins at doses of 5 and 10 mg/kg 35 and 56 days after ethane dimethane sulfonate. Using a 3D seminiferous tubule culture system to study the development of stem Leydig cells, we found that perfluorooctane sulfonate inhibited stem Leydig cell proliferation and differentiation and hedgehog signaling pathway. In conclusion, a short-term exposure to perfluorooctane sulfonate can inhibit the development of stem Leydig cells into the Leydig cell lineage via direct suppression of hedgehog signaling pathway and indirect inhibition of desert hedgehog section by Sertoli cells.
Topics: Alkanesulfonic Acids; Animals; Cell Differentiation; Cell Proliferation; Fluorocarbons; Hedgehog Proteins; Male; Mesylates; Rats, Sprague-Dawley; Regeneration; Signal Transduction; Testis; Testosterone; Rats
PubMed: 33721578
DOI: 10.1016/j.ecoenv.2021.112121 -
BMC Genetics Aug 2020Lesion-mimic and premature aging (lmpa) mutant lmpa1 was identified from the ethyl methane sulfonate (EMS) mutant library in the bread wheat variety Keda 527 (KD527)...
BACKGROUND
Lesion-mimic and premature aging (lmpa) mutant lmpa1 was identified from the ethyl methane sulfonate (EMS) mutant library in the bread wheat variety Keda 527 (KD527) background. To reveal the genetic basis of lmpa1 mutant, phenotypic observations and analyses of chlorophyll content and photosynthesis were carried out in lmpa1, KD527 and their F and F derivatives. Further, bulked segregation analysis (BSA) in combination with a 660 K SNP array were conducted on the F segregation population of lmpa1/Chinese spring (CS) to locate the lmpa1 gene.
RESULTS
Most agronomic traits of lmpa1 were similar to those of KD527 before lesion-like spots appeared. Genetic analysis indicated that the F plants from the crossing of lmpa1 and KD527 exhibited the lmpa phenotype and the F progenies showed a segregation of normal (wild type, WT) and lmpa, with the ratios of lmpa: WT = 124:36(χ = 1.008 < =3.841), indicating that lmpa is a dominant mutation. The combination of BSA and the SNP array analysis of CS, lmpa1 and lmpa1/CS F WT pool (50 plants) and lmpa pool (50 plants) showed that polymorphic SNPs were enriched on chromosome 5A, within a region of 30-40 Mb, indicating that the wheat premature aging gene Lmpa1 was probably located on the short arm of chromosome 5A.
CONCLUSIONS
EMS-mutagenized mutant lmpa1 deriving from elite wheat line KD527 conferred lmpa. Lmpa phenotype of lmpa1 mutant is controlled by a single dominant allele designated as Lmpa1, which affected wheat growth and development and reduced the thousand grain weight (tgw) of single plant in wheat. The gene Lmpa1 was tentatively located within the region of 30-40 Mb near to the short arm of chromosome 5A.
Topics: Alleles; Chlorophyll; Chromosome Mapping; Ethyl Methanesulfonate; Genes, Plant; Mutagens; Phenotype; Photosynthesis; Polymorphism, Single Nucleotide; Triticum
PubMed: 32807077
DOI: 10.1186/s12863-020-00891-x -
Pharmaceutical Biology Dec 2023di-(2-Ethylhexyl) phthalate (DEHP) has potential reproductive toxicity. Bu-Shen-Tian-Jing formulations (BSTJFs) are beneficial for female reproductive capacity. However,...
CONTEXT
di-(2-Ethylhexyl) phthalate (DEHP) has potential reproductive toxicity. Bu-Shen-Tian-Jing formulations (BSTJFs) are beneficial for female reproductive capacity. However, BSTJF2 has much lower cytotoxicity than BSTJF1.
OBJECTIVE
To investigate the effects of BSTJFs on ovarian granulosa cells exposed to DEHP and determine the potential molecular mechanisms.
METHODS AND MATERIALS
Human granulosa-like tumor cell line (KGN) cells were divided into control, DEHP, BSTJF1 and BSTJF2 groups. The DEHP group were given 1 μM DEHP for 24 h. They were then given BSTJF1 at 200 μg/mL or BSTJF2 at 100 μg/mL for 24 h. The control group was treated with the same concentration of DMSO (0.1%). Oxidative stress and mitochondrial function were measured. The mRNA and protein expression levels of HDAC3 and HSP90AA were determined. Integrative network pharmacology analysis of BSTJF2 was also performed.
RESULTS
DEHP (1 μM) significantly suppressed the proliferation of KGN cells by 17%, significantly increased ROS levels by 28% and MDA levels by 47%, significantly decreased MMP levels by 22% and mtDNA copy by 30%. DEHP significantly increased protein expression of HDAC3 by 21%and HSP90AA by 64%. All these changes were significantly reversed by BSTJFs. Integrative network pharmacology analysis revealed HSP90AA was a key target (degree = 8). Both RGFP966 and BSTJF2 significantly reversed the increased expression of HDAC3 and HSP90AA, attenuated oxidative stress, and mitochondrial damage which were induced by DEHP.
CONCLUSION
BSTJFs might have therapeutic potential on oxidative stress and mitochondrial damage through the HDAC3/HSP90AA pathway which encourages further clinical trials.
Topics: Humans; Female; Diethylhexyl Phthalate; Oxidative Stress; Granulosa Cells; Busulfan; Cell Line, Tumor
PubMed: 37655754
DOI: 10.1080/13880209.2023.2249193 -
Plant Biotechnology Journal Jan 2023Tiller angle is one of the most important agronomic traits and one key factor for wheat ideal plant architecture, which can both increase photosynthetic efficiency and...
Tiller angle is one of the most important agronomic traits and one key factor for wheat ideal plant architecture, which can both increase photosynthetic efficiency and greatly enhance grain yield. Here, a deacetylase HST1-like (TaHST1L) gene controlling wheat tiller angle was identified by the combination of a genome-wide association study (GWAS) and bulked segregant analysis (BSA). Ethyl methane sulfonate (EMS)-mutagenized tetraploid wheat lines with the premature stop codon of TaHST1L exhibited significantly smaller tiller angles than the wild type. TaHST1L-overexpressing (OE) plants exhibited significantly larger tiller angles and increased tiller numbers in both winter and spring wheat, while TaHST1L-silenced RNAi plants displayed significantly smaller tiller angles and decreased tiller numbers. Moreover, TaHST1L strongly interacted with TaIAA17 and inhibited its expression at the protein level, and thus possibly improved the content of endogenous auxin in the basal tissue of tillers. The transcriptomics and metabolomics results indicated that TaHST1L might change plant architecture by mediating auxin signal transduction and regulating endogenous auxin levels. In addition, a 242-bp insertion/deletion (InDel) in the TaHST1L-A1 promoter altered transcriptional activity and TaHST1L-A1b allele with the 242-bp insertion widened the tiller angle of TaHST1L-OE transgenic rice plants. Wheat varieties with TaHST1L-A1b allele possessed the increased tiller angle and grain yield. Further analysis in wheat and its progenitors indicated that the 242-bp InDel possibly originated from wild emmer and was strongly domesticated in the current varieties. Therefore, TaHST1L involved in the auxin signalling pathway showed the big potential to improve wheat yield by controlling plant architecture.
Topics: Indoleacetic Acids; Triticum; Plant Proteins; Genome-Wide Association Study; Alleles; Edible Grain; Oryza
PubMed: 36128872
DOI: 10.1111/pbi.13930 -
Cellular and Molecular Life Sciences :... Aug 2023Human erythroleukemic K562 cells represent the prototypical cell culture model of chronic myeloid leukemia (CML). The cells are pseudo-triploid and positive for the...
Human erythroleukemic K562 cells represent the prototypical cell culture model of chronic myeloid leukemia (CML). The cells are pseudo-triploid and positive for the Philadelphia chromosome. Therefore, K562 cells have been widely used for investigating the BCR/ABL1 oncogene and the tyrosine kinase inhibitor, imatinib-mesylate. Further, K562 cells overexpress transferrin receptors (TfR) and have been used as a model for targeting cytotoxic therapies, via receptor-mediated endocytosis. Here, we have characterized K562 cells focusing on the karyotype of cells in prolonged culture, regulation of expression of TfR in wildtype (WT) and doxorubicin-resistant cells, and responses to histone deacetylase inhibition (HDACi). Karyotype analysis indicates novel chromosomes and gene expression analysis suggests a shift of cultured K562 cells away from patient-derived leukemic cells. We confirm the high expression of TfR on K562 cells using immunofluorescence and cell-surface receptor binding radioassays. Importantly, high TfR expression is observed in patient-derived cells, and we highlight the persistent expression of TfR following doxorubicin acquired resistance. Epigenetic analysis indicates that permissive histone acetylation and methylation at the promoter region regulates the transcription of TfR in K562 cells. Finally, we show relatively high expression of HDAC enzymes in K562 cells and demonstrate the chemotoxic effects of HDACi, using the FDA-approved hydroxamic acid, vorinostat. Together with a description of morphology, infrared spectral analysis, and examination of metabolic properties, we provide a comprehensive characterization of K562 cells. Overall, K562 cell culture systems remain widely used for the investigation of novel therapeutics for CML, which is particularly important in cases of imatinib-mesylate resistance.
Topics: Humans; Imatinib Mesylate; K562 Cells; Fusion Proteins, bcr-abl; Transferrin; Pyrimidines; Drug Resistance, Neoplasm; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Histone Deacetylases; Doxorubicin; Receptors, Transferrin; Chromosomes; Mesylates; Apoptosis
PubMed: 37578596
DOI: 10.1007/s00018-023-04905-6 -
Turkish Journal of Medical Sciences Feb 2023Since well-designed prospective comparative trials are lacking, haploidentical hematopoietic stem cell transplantations approach should be based on the expertise of a...
BACKGROUND
Since well-designed prospective comparative trials are lacking, haploidentical hematopoietic stem cell transplantations approach should be based on the expertise of a particular center. In this study, we aimed to report the results and outcomes of patients who underwent haploidentical hematopoietic stem cell transplantation.
METHODS
: Thirty-nine patients who underwent transplantation in our clinic between 2015 and 2022 were retrospectively analyzed. Primary end point of this study is to find out the survival rates of the patients.
RESULTS
The overall survival of patients was 29.9 ± 4.9 months. The disease-free survival of the patients was 37.8 ± 5.7 months. The 3-year overall survival rate of the patients was %50 and the 3-year disease-free survival rate of the patients was %53. Nineteen patients were nonsurvivors among a total of 39 patients. Busulfan-fludarabine-thiotepa was the most frequently used conditioning regimen for transplantation. Busulfan-fludarabin-antithymocyte globulin regimen is the second preferred conditioning regimen. Cyclosporine- cyclophosphamide-mycophenolate mofetil was the most widely used graft-versus-host disease prophylaxis regimen. Sixteen patients had graft-versus-host disease, 28% of the patients had acute graft-versus-host disease, and 13% had chronic graft-versus-host disease. Gastrointestinal system consists of the most involved organs in graft-versus-host disease since 15% of the patients had gastrointestinal graft-versus-host disease. First-degree relatives (parent/child) were the most frequent donor source for haploidentical hematopoietic stem cell transplantation. Sepsis was the most frequent reason of death among transplant patients.
DISCUSSION
In our center, we prefer to use high dose posttransplantation cyclophosphamide after haploidentical hematopoietic stem cell transplantation for graft-versus-host disease prophylaxis. With this approach, our center's overall survival and disease-free survival rates are comparable and compatible with the literature findings.
Topics: Child; Humans; Busulfan; Retrospective Studies; Prospective Studies; Hematopoietic Stem Cell Transplantation; Cyclophosphamide; Cyclosporine; Graft vs Host Disease; Mycophenolic Acid; Hematologic Neoplasms
PubMed: 36945951
DOI: 10.55730/1300-0144.5591 -
Archives of Razi Institute Jun 2023Rasagiline is a selective and irreversible inhibitor of monoamine oxidase B (MAO-B) that is effective in the treatment of Parkinson's disease (PD). It had antioxidant...
Rasagiline is a selective and irreversible inhibitor of monoamine oxidase B (MAO-B) that is effective in the treatment of Parkinson's disease (PD). It had antioxidant and anti-apoptotic activity in experimental models. Moreover, it has low permeability and its oral bioavailability is weak and highly variable due to extensive first-pass hepatic metabolism (35%). This study aimed to formulate rasagiline mesylate (RM) as a lipid-polymer hybrid nanoparticle in order to enhance its permeation and increase its chance to be absorbed by lymphatic circulation to avoid metabolism and control its release. Successful formulation (PCL-2) was reached by the nanoprecipitation method using polycaprolactone with RM in the organic phase and lecithin in the aqueous phase DSPE-PEG. The lipid:polymer ratio of 24% and DSPE: lecithin of 50% resulted in stable nanoparticles having a particle size of 132±4.58 nm, polydispersity index of 0.273±0.02, zeta potential of -25.6±3.3, entrapment efficiency of 46±3.9%, and drug loading of 51.93±6.5. Results showed that the diffusion was more effective on the release profile than the degradation and resulted in a Fickian diffusion mechanism.
Topics: Animals; Monoamine Oxidase Inhibitors; Lecithins; Neuroprotective Agents; Mesylates
PubMed: 38028832
DOI: 10.22092/ARI.2022.360193.2563 -
Journal of Aerosol Medicine and... Dec 2022Oral tablets account for the majority of medications used to acutely treat migraine, but relief can be limited by their rates of dissolution and absorption. The nose is... (Review)
Review
Oral tablets account for the majority of medications used to acutely treat migraine, but relief can be limited by their rates of dissolution and absorption. The nose is an attractive alternative route of drug delivery since it provides patient convenience of at-home use, gastrointestinal (GI) avoidance, and rapid absorption of drugs into systemic circulation because of its large surface area. However, the site of drug deposition within the nasal cavity should be considered since it can influence drug absorption. Traditional nasal devices have been shown to target drug delivery to the lower nasal space where epithelium is not best-suited for drug absorption and where there is an increased likelihood of drug clearance due to nasal drip, swallowing, or mucociliary clearance, potentially resulting in variable absorption and suboptimal efficacy. Alternatively, the upper nasal space (UNS) offers a permeable, richly vascularized epithelium with a decreased likelihood of drug loss or clearance due to the anatomy of this area. Traditional nasal pumps deposit <5% of active drug into the UNS because of the nasal cavity's complex architecture. A new technology, Precision Olfactory Delivery (POD), is a handheld, manually actuated, propellant-powered, administration device that delivers drug specifically to the UNS. A dihydroergotamine (DHE) mesylate product, INP104, utilizes POD technology to deliver drug to the UNS for the acute treatment of migraine. Results from clinical studies of INP104 demonstrate a favorable pharmacokinetic profile, consistent and predictable dosing, rapid systemic levels known to be effective (similar to other DHE mesylate clinical programs), safety and tolerability on the upper nasal mucosa, and high patient acceptance. POD technology may have the potential to overcome the limitations of traditional nasal delivery systems, while utilizing the nasal delivery benefits of GI tract avoidance, rapid onset, patient convenience, and ease of use.
Topics: Humans; Dihydroergotamine; Administration, Intranasal; Administration, Inhalation; Migraine Disorders; Technology; Mesylates
PubMed: 36108289
DOI: 10.1089/jamp.2022.0005