Epigenetic modifications affect gene expression without changes in the actual DNA sequence. Two of the most important mechanisms include DNA methylation and histone tail modifications (especially ...acetylation and methylation). Epigenetic modulation is a part of normal physiologic development; its dysregulation is an important mechanism of pathogenesis of some cancers, including acute myeloid leukemia (AML). Despite significant progress in understanding the pathogenesis of AML, therapeutic options remain quite limited. Technological advances have facilitated understanding of aberrant DNA methylation and histone methylation/acetylation as key elements in the development of AML and uncovered several recurrent mutations in genes important for epigenetic regulation. However, much remains to be learned about how to exploit this knowledge for epigenetic therapeutic targeting. Currently, no epigenetic therapy is approved for the treatment of AML, although two DNA methyltransferase inhibitors (azacitidine and decitabine) are commonly used in clinical practice. Among the other epigenetic modifiers undergoing research in AML, the histone deacetylase inhibitors are the most studied. Other promising drugs, such as inhibitors of histone methylation (eg, EZH2 and DOT1L inhibitors), inhibitors of histone demethylases (eg, LSD1 inhibitors), inhibitors of bromodomain-containing epigenetic "reader" BET proteins, and inhibitors of mutant isocitrate dehydrogenases, are at early stages of clinical evaluation.
Polydimethylsiloxane (PDMS) is used in implantable medical devices; however, PDMS is not a completely biocompatible material for electronic medical devices in the bladder. To identify novel ...biocompatible materials for intravesical implanted medical devices, we evaluated the biocompatibility of polymethyl methacrylate (PMMA) by analyzing changes in the levels of macrophages, macrophage migratory inhibitory factor (MIF), and inflammatory cytokines in the bladder. A ball-shaped metal coated with PMMA or PDMS was implanted into the bladders of rats, and after intravesical implantation, the inflammatory changes induced by the foreign body reaction were evaluated. In the early period after implantation, increased macrophage activity and MIF in the urothelium of the bladder were observed. However, significantly decreased macrophage activity and MIF in the bladder were observed after implantation with PMMA- or PDMS-coated metal in the later period. In addition, significantly decreased inflammatory cytokines such as IL-1β, IL-6, and TNF-α were observed with time. Based on these results, we suggest that MIF plays a role in the foreign body reaction and in the biocompatible packaging with PMMA for the implanted medical devices in the bladder.
For several decades, we have known that epigenetic regulation is disrupted in cancer. Recently, an increasing body of data suggests epigenetics might be an intersection of current cancer research ...trends: next generation sequencing, immunology, metabolomics, and cell aging. The new emphasis on epigenetics is also related to the increasing production of drugs capable of interfering with epigenetic mechanisms and able to trigger clinical responses in even advanced phase patients. In this review, we will use myeloid malignancies as proof of concept examples of how epigenetic mechanisms can trigger or promote oncogenesis. We will also show how epigenetic mechanisms are related to genetic aberrations, and how they affect other systems, like immune response. Finally, we will show how we can try to influence the fate of cancer cells with epigenetic therapy.
This study aimed to validate the new European Leukemia Net (ELN) 2022 criteria for genetic risk stratification in older adults with acute myeloid leukemia (AML) and to determine the most likely set ...of clusters of similar cytogenetic and mutation properties correlated with survival outcomes in three treatment groups: intensive chemotherapy (IC), hypomethylating agents (HMA) alone, and HMA plus venetoclax (HMA/VEN). The study included 279 patients (aged ≥60 years) who received IC (N=131), HMA (N=76), and HMA/VEN (N=72) between July 2017 and October 2021. No significant differences were observed in survival among the groups according to ELN 2022 risk stratification. Unsupervised hierarchical clustering analysis identified nine genomic clusters (C1-9) with varying survival outcomes depending on treatment type. For example, C4 (predominant for core binding factor-AML) displayed a favorable prognosis in the IC group, but not in the HMA or HMA/VEN groups. The HMA/VEN group had better outcomes than the HMA group in many clusters (C1, 2, 3, and 5); however, the addition of VEN to HMA or IC did not improve the survival outcomes compared with those of HMA alone in C7 and C9 (predominant for -5, del(5q), -7, -17/abn(17p), complex karyotypes, and mutated TP53). The study highlights the limitations of ELN genetic risk stratification in older adults with AML. It emphasizes the need for a more comprehensive approach that considers co-occurring somatic mutations to guide treatment selection in older adults with AML.
Recently, because of the influence of climate change on sea level change, there has been growing concern regarding the erosion of beaches, which play a role in reducing the damage caused by coastal ...disasters. However, despite these concerns, a comprehensive understanding of the morphodynamic relationship between hazard factors and beach erosion is still lacking. Therefore, in this study, a vulnerability analysis of beach erosion was conducted by applying the shoreline response model (SLRM) of bulk model type, which identifies the physical characteristics of relevant coefficients based on the suspended sediment movement processes. To characterize wave energy incidence, storm wave scenario modeling and extreme wave analysis were conducted using wave data of 40 years on the east coast of Korea provided by the National Oceanic and Atmospheric Administration. A dimensionless mathematical function representing the storm wave scenario was proposed as a function of the peak wave height. In addition, to examine whether the beach vulnerability curve (BVC) obtained from the SLRM is valid, it was compared with the long-term shoreline observation data conducted at Maengbang Beach. For the past 9 years, sand sampling and shoreline observations were performed at Maengbang Beach about 5 times a year. However, since observations were performed in time intervals of several months, the direct comparison with model results was impossible, so a comparative analysis through statistical analysis of shoreline variability was performed. The variability of the shoreline for each reference point followed a normal distribution with a standard deviation of approximately 7.1 m. As a result of comparing the BVC results obtained from these statistical characteristics with those obtained from the model, significant similarity was shown in the high wave condition. Finally, the model was performed on two factors (mean wave height and peak wave height) which appear in SWSF and three factors (wave energy at breaking point, beach response factor and beach recovery factor) which appear in SLRM, and by analyzing the results, an approximate formula for the BVC is derived. This novel BVC approximation equation provides an intuitive understanding of the factors that affect beach vulnerability as well as their importance, and estimates the beach buffer section required to prevent coastal facilities from being damaged by erosion during a specific period. The results of this study can help limit reckless coastal development and mitigate erosion damage.
Cavernous nerve injury is the main reason for post‐prostatectomy erectile dysfunction (ED). Stem cell and neuroprotection therapy are promising therapeutic strategy for ED.
To evaluate the ...therapeutic efficacy of adipose‐derived stem cells (ADSCs) and brain‐derived neurotrophic factor (BDNF) immobilized Poly‐Lactic‐Co‐Glycolic (PLGA) membrane on the cavernous nerve in a rat model of post‐prostatectomy ED.
Rats were randomly divided into five groups: normal group, bilateral cavernous nerve crush injury (BCNI) group, ADSC (BCNI group with ADSCs on cavernous nerve) group, BDNF‐membrane (BCNI group with BDNF/PLGA membrane on cavernous nerve) group, and ADSC/BDNF‐membrane (BCNI group with ADSCs covered with BDNF/PLGA membrane on cavernous nerve) group. BDNF was controlled‐released for a period of 4 weeks in a BDNF/PLGA porous membrane system.
Four weeks after the operation, erectile function was assessed by detecting the ratio of intra‐cavernous pressure (ICP)/mean arterial pressure (MAP). Smooth muscle and collagen content were determined by Masson's trichrome staining. Neuronal nitric oxide synthase (nNOS) expression in the dorsal penile nerve was detected by immunostaining. Phospho‐endothelial nitric oxide synthase (eNOS) protein expression and cyclic guanosine monophosphate (cGMP) level of the corpus cavernosum were quantified by Western blotting and cGMP assay, respectively.
In the ADSC/BDNF‐membrane group, erectile function was significantly elevated, compared with the BCNI and other treated groups. ADSC/BDNF‐membrane treatment significantly increased smooth muscle/collagen ratio, nNOS content, phospho‐eNOS protein expression, and cGMP level, compared with the BCNI and other treated groups.
ADSCs with BDNF‐membrane on the cavernous nerve can improve erectile function in a rat model of post‐prostatectomy ED, which may be used as a novel therapy for post‐prostatectomy ED. Piao S, Kim IG, Lee JY, Hong SH, Kim SW, Hwang T‐K., Heang S, Lee JH, Ra JC, and Lee JY. Therapeutic effect of adipose‐derived stem cells and BDNF‐immobilized PLGA membrane in a rat model of cavernous nerve injury. J Sex Med 2012;9:1968–1979.
Ionic liquids (ILs) have attracted significant interest because of their desirable properties. These characteristics have improved their application to overcome the shortcomings of conventional ...separation techniques for phytochemicals. In this study, several ILs were investigated for their capacity to extract isoimperatorin, a bioactive furanocoumarin, from the roots of
. Herein, 1-Butyl-3-methylimidazolium tetrafluoroborate (BmimBF
) was selected as a promising IL for separating isoimperatorin. A central composite design was applied to optimize the extraction conditions. Under the optimal conditions, the yield of isoimperatorin reached 97.17 ± 1.84%. Additionally, the recovery of isoimperatorin from the BmimBF
solution was successfully achieved (87.73 ± 2.37%) by crystallization using water as an antisolvent. The purity of the isoimperatorin was greatly enhanced, from 0.26 ± 0.28% in the raw material to 26.94 ± 1.26% in the product, in a one-step crystallization process. Namely, an enhancement of approximately 103-folds was reached. The developed approach overcomes the shortcomings of conventional separation methods applied for gaining isoimperatorin by significantly reducing the laboriousness of the process and the consumption of volatile organic solvents. Moreover, the simplicity and effectiveness of the method are assumed to be valuable for producing isoimperatorin-enriched products and for promoting its purification. This work also confirms the efficiency of ILs as a promising material for the separation of phytochemicals.
Immunosuppressive strategies currently used in hematopoietic stem cell transplantation reliably decrease graft-versus-host disease (GVHD) rates, but also impair pathogen-specific immunity. ...Experimental transplant studies indicate that GVHD-initiating alloreactive T cells reside primarily in naive and central memory T-cell compartments. In contrast, virus-specific T cells comprise a more differentiated memory population. After finding that the rat sarcoma/mitogen-activated protein kinase kinase/extracellular receptor kinase (RAS/MEK/ERK) pathway is preferentially activated in naive and central memory human T cells, we hypothesized that MEK inhibitors would preferentially inhibit alloreactive T cells, while sparing more differentiated virus-specific T cells. Confirming our hypothesis, we found that MEK inhibitors including selumetinib preferentially inhibited cytokine production and alloreactivity mediated by naive and central memory human CD4+ and CD8+ T cells while sparing more differentiated T cells specific for the human herpesviruses cytomegalovirus and Epstein-Barr virus. We then demonstrated that short-term posttransplant administration of selumetinib in a major histocompatibility complex major- and minor-mismatched murine model significantly delayed the onset of GVHD-associated mortality without compromising myeloid engraftment, demonstrating the in vivo potential of MEK inhibitors in the setting of hematopoietic stem cell transplantation. These findings demonstrate that targeting memory-dependent differences in T-cell signaling is a potent and selective approach to inhibition of alloreactivity.
•RAS/MEK/ERK signaling is memory stage-dependent in human T cells, conferring susceptibility to alloreactive T-cell selective inhibition.•MEK inhibitors selectively inhibit alloreactive but not herpesvirus-specific human T cells and inhibit murine GVHD.
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