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Recent advances of chimeric antigen receptor T-cell therapy for acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogeneously primary hematopoietic neoplasm characterized by uncontrolled proliferation of immature myeloid cells, which is characterized with poor outcomes. Despite tremendous advances in the treatment paradigm of AML in the past several decades, the cure and prognosis remain unfavorable. More effective treatments are therefore needed to improve the clinical outcomes. Among newly emerging immunotherapies, chimeric antigen receptor (CAR)-T cell immunotherapy is an exceedingly promising approach that has remarkably improved the overall survival for patients

Role of B-Cell in the Pathogenesis of Systemic Sclerosis.

Systemic sclerosis (SSc) is a rare multisystem autoimmune disease, characterized by fibrosis, vasculopathy, and autoimmunity. Recent advances have highlighted the significant implications of B-cells in SSc. B-cells are present in affected organs, their subpopulations are disrupted, and they display an activated phenotype, and the regulatory capacities of B-cells are impaired, as illustrated by the decrease in the IL-10+ producing B-cell subpopulation or the inhibitory membrane co-receptor density. Recent multi-omics evidence highlights the role of B-cells mainly in the early stage of SSc and p

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… However, the CD70 promoter is demethylated, favoring its overexpression on CD4+ T cells and seems to have contributed to the autoimmune response via its costimulatory activity of the B-cell during the B–T cell interaction ( 95 ). … Demethylation of TNFSF7 Contributes to CD70 Overexpression in CD4+ T Cells From Patients With Systemic Sclerosis . Clin Immunol ( 2012 ) 143 : 39 – 44 . doi: 10.1016/j.clim.2012.01.005 22306512 96 Fuschiotti P . Current Perspectives on the Role of CD8+ T Cells in Systemic Sclerosis . …

Prodrugs in Oncology: Bioactivation and Impact on Therapeutic Efficacy and Toxicity.

A prodrug is a molecule that lacks pharmacological activity, but upon enzymatic bioactivation, it can generate a therapeutically active molecule. The primary reason behind the design of a prodrug is to help circumvent challenges associated with the physicochemical properties of a drug molecule, such as solubility, absorption, distribution, and instability. Chemotherapy has been at the forefront of cancer treatment for over 70 years due to its ability to target rapidly proliferating tumor cells. However, a major concern with conventional chemotherapy is the lack of selectivity and its associate

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… As shown in Figure 3 , dacarbazine first undergoes a CYP-mediated N-demethylation to form the reactive species 5-[3-hydroxy methyl-3-methyl-triazen-l-yl]-imidazole-4-carboxamide (HMMTIC). … Saturable enzyme kinetics for CYP1A1 and CYP1A2 were not observed in human microsomal systems, so individual cDNA enzymes were used to define the enzyme kinetics of dacarbazine N-demethylation. …

RNA метилтрансферазы METTL8 устанавливает m3C32 в митохондриальном tRNASThr/Ser (UCN) для оптимизации структуры trNA и митохондриального перевода.

Модифицированные нуклеотиды в tRNA являются важными определяющими факторами сворачивания, структуры и функции. Здесь мы идентифицируем METTL8 как митохондриальный белок и активный РНК метилтрансферазы, ответственный за установку m3C32 в митохондриале человека (mt-)tRNAThr и mt-tRNAser (UCN). METTL8 имеет перекрестные связи с антикодоновой стволовой петлей (ASL) многих мт-тРНК в клетках, в связи с чем возникает вопрос о том, каким образом достигается целевая специфичность метилирования. Расчленение элементов распознавания mt-tRNA выявило наличие U34G35 и t6A37/(ms2)i6A37, которые одновременно п

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… mt-tRNA Thr/Ser(UCN) and our reconstitution of METTL8 methylation on cellular RNAs indicate that these modifications are not fully stoichiometric, raising the possibility that mitochondrial translation could be regulated by differentially modified mt-tRNA Thr/Ser(UCN) . m 3 C in RNAs can be actively demethylated … However, ALKBH3 is not present in mitochondria 45 and no changes in m 3 C 32 levels in mt-tRNA Thr/Ser(UCN) were observed in in vitro demethylation assays using purified ALKBH1 and m 3 C-containing synthetic anticodon stem loops (Supplementary Fig. 8 ). …

Pharmacological treatment options for mast cell activation disease.

Mast cell activation disease (MCAD) is a term referring to a heterogeneous group of disorders characterized by aberrant release of variable subsets of mast cell (MC) mediators together with accumulation of either morphologically altered and immunohistochemically identifiable mutated MCs due to MC proliferation (systemic mastocytosis [SM] and MC leukemia [MCL]) or morphologically ordinary MCs due to decreased apoptosis (MC activation syndrome [MCAS] and well-differentiated SM). Clinical signs and symptoms in MCAD vary depending on disease subtype and result from excessive mediator release by MC

Confirmatory Trials in the Evaluation of Anticancer Medicinal Products in Man--PFS2: A Measure of Therapeutic Action-At-A-Distance.

Overall survival (OS) has emerged as the definitive regulatory "be-all, end-all" for the demonstration of benefit in cancer clinical trials. The reason and the rationale for why this is so are easily appreciated: literally a "test of time," OS is a seemingly unambiguous, agenda-free end point, independent of bias-prone variables such as the frequency and methods of assessment, clinical evaluation, and the definition of progression. However, by general consensus, OS is an imperfect end point for several reasons: First, it may often be impractical because of the length, cost, and the size of cli

Repurposing Drugs for Acute Myeloid Leukemia: A Worthy Cause or a Futile Pursuit?

Acute myeloid leukemia (AML) is a clinically and genetically heterogenous malignancy of myeloid progenitor cells that affects patients of all ages. Despite decades of research and improvement in overall outcomes, standard therapy remains ineffective for certain subtypes of AML. Current treatment is intensive and leads to a number of secondary effects with varying results by patient population. Due to the high cost of discovery and an unmet need for new targeted therapies that are well tolerated, alternative drug development strategies have become increasingly attractive. Repurposing existing d

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… Interestingly, demethylation of genes involved in the progression of MDS to AML (FZD9, ALOX12, HPN, and CALCA) was related to clinical response. … LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription Nature 2005 437 436 439 10.1038/nature04020 16079795 79. Huang J. Sengupta R. Espejo A.B. Lee M.G. Dorsey J.A. Richter M. Opravil S. Shiekhattar R. Bedford M.T. …

Clinical outcomes of chemotherapy in cancer patients with different ethnicities.

BackgroundChoosing the most effective chemotherapeutic agent with safest side effect profile is a common challenge in cancer treatment. Although there are standardized chemotherapy protocols in place, protocol changes made after extensive clinical trials demonstrate significant improvement in the efficacy and tolerability of certain drugs. The pharmacokinetics, pharmacodynamics, and tolerance of anti-cancer medications are all highly individualized. A driving force behind these differences lies within a person's genetic makeup.Recent findingsPharmacogenomics, the study of how an individual's g

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… Drug | Route, dosage form and dose (human) | Pharmacokinetics (PK) | Pharmacodynamics (PD) | Ethnic variability of PK/PD Altretamine | Oral Capsule; 260 mg/m 2 /day | A: Well‐absorbed D: Highly concentrated in the liver, kidney, & small intestine Tmax: 0.5–3 h t 1/2 : 7 h M: Liver; extensive demethylation … Cytochrome‐P450 (CYP) enzymes are primarily responsible for metabolizing TKI by phase I and UDP‐glucuronosyltransferases (UGTs) by phase II reactions. 142 The enzyme CYP3A4 is principally responsible for metabolism of sunitinib and imatinib into the biologically active metabolites N‐desethyl (SU12662) and N‐demethylated …

Pharmacological Treatments and Therapeutic Drug Monitoring in Patients with Chronic Pain.

Pain is an unpleasant sensory and emotional experience that affects every aspect of a patient's life and which may be treated through different pharmacological and non-pharmacological approaches. Analgesics are the drugs most commonly used to treat pain, and in specific situations, the use of opioids may be considered with caution. These drugs, in fact, do not always induce optimal analgesia in patients, and several problems are associated with their use. The purpose of this narrative review is to describe the pharmacological approaches currently used for the management of chronic pain. We rev

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… This drug undergoes partial first pass metabolism in the liver by N - and O -demethylation and conjugation. … O -demethylation of tramadol produces O -desmethyltramadol (M1) and is catalyzed by CYP2D6, whereas N -demethylation to N -desmethyltramadol (M2) is catalyzed by CYP3A4 and CYP2B6 [ 107 , 108 , 109 , 110 ] ( Figure 3 ). …

Glioblastoma Treatment: State-of-the-Art and Future Perspectives.

(1) Background: Glioblastoma is the most frequent and lethal primary tumor of the central nervous system. Through many years, research has brought various advances in glioblastoma treatment. At this time, glioblastoma management is based on maximal safe surgical resection, radiotherapy, and chemotherapy with temozolomide. Recently, bevacizumab has been added to the treatment arsenal for the recurrent scenario. Nevertheless, patients with glioblastoma still have a poor prognosis. Therefore, many efforts are being made in different clinical research areas to find a new alternative to improve ove

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… S-methyl-L-cysteine is the end product of a methylated-DNA-cysteine S-methyltransferase mediated demethylation process of DNA containing methylguanine. … S-methyl-Lcysteine levels in tumor tissue drop after RT, suggesting that the treatment interferes with the methylated-DNA-cysteine S-methyltransferase-mediated demethylation process [ 36 ]. 4.3. …

Refractory Hyperammonemic Encephalopathy as a Paraneoplastic Presentation of Fibrolamellar Hepatocellular Carcinoma: A Case Report.

BACKGROUND Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare liver malignancy affecting adolescents and young adults without underlying liver disease. Hyperammonemic encephalopathy (HAE) is an uncommon but severe complication in advanced FLHCC, resulting from progressive hepatic dysfunction or tumor-related metabolic derangements. Early recognition is essential to prevent neurologic decline and improve outcomes. CASE REPORT A 24-year-old man with metastatic FLHCC presented with worsening confusion for 1 month. His prior treatments included transarterial radioembolization, multiple resec

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… 36423742 10.1016/j.ijrobp.2022.11.022 20 Lin CP Liu CR Lee CN Targeting c-Myc as a novel approach for hepatocellular carcinoma World J Hepatol 2010 2 1 16 20 21160952 10.4254/wjh.v2.i1.16 PMC2999263 21 Bott AJ Peng IC Fan Y Oncogenic Myc induces expression of glutamine synthetase through promoter demethylation …

Targeting Histone Epigenetic Modifications and DNA Damage Responses in Synthetic Lethality Strategies in Cancer?

Synthetic lethality strategies are likely to be integrated in effective and specific cancer treatments. These strategies combine different specific targets, either in similar or cooperating pathways. Chromatin remodeling underlies, directly or indirectly, all processes of tumor biology. In this context, the combined targeting of proteins associated with different aspects of chromatin remodeling can be exploited to find new alternative targets or to improve treatment for specific individual tumors or patients. There are two major types of proteins, epigenetic modifiers of histones and nuclear o

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… LSD1 demethylates H3K4m3 and K3K9me and regulates anti-tumor immune responses [ 73 ]. Depletion of LSD1 enhances tumor immunogenicity, facilitates T cell infiltration and causes a significant response in melanomas that are refractory to anti-PD-L1 blockade [ 73 ]. … radiation Olaparib | - Lung cancer Metastatic melanoma, Ovarian resistant to PARP inhibitors | [ 138 , 139 , 140 ] DNA-PK | Peposertib (M3814) AZD7648 | - Olaparib | Rectal cancer | [ 141 , 142 ] CDK4/6 | trilaciclib | Platinum/etoposide topotecan | ES-SCLC | [ 143 ] Figure 3 Effect methylation and demethylation …

Transplantation Tolerance through Hematopoietic Chimerism: Progress and Challenges for Clinical Translation.

The perception that transplantation of hematopoietic stem cells can confer tolerance to any tissue or organ from the same donor is widely accepted but it has not yet become a treatment option in clinical routine. The reasons for this are multifaceted but can generally be classified into safety and efficacy concerns that also became evident from the results of the first clinical pilot trials. In comparison to standard immunosuppressive therapies, the infection risk associated with the cytotoxic pre-conditioning necessary to allow allogeneic bone marrow engraftment and the risk of developing gra

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… These Tregs exhibited an increased surface expression of GITR and CD39 together with a decreased demethylation of the Treg-specific demethylated region ( 133 ). …

The Cancer Antioxidant Regulation System in Therapeutic Resistance.

Antioxidants play a pivotal role in neutralizing reactive oxygen species (ROS), which are known to induce oxidative stress. In the context of cancer development, cancer cells adeptly maintain elevated levels of both ROS and antioxidants through a process termed "redox reprogramming". This balance optimizes the proliferative influence of ROS while simultaneously reducing the potential for ROS to cause damage to the cell. In some cases, the adapted antioxidant machinery can hamper the efficacy of treatments for neoplastic diseases, representing a significant facet of the resistance mechanisms ob

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… of NFE2L2 promoter | [ 77 ] Lung cancer | NA | EZH2 deficiency caused demethylation of histone H3K27, which promoted transcription of NRF2 | [ 78 ] Translational alterations HCC | 5-Fluorouracil | MiR-144(-3p), a microRNA that degraded NRF2 mRNA effectively, was lower in cancer cells compared with normal … Conversely, a demethylation status of the NEF2L2 promoter was found in colorectal tumor samples [ 77 ]. …

Tales from the Jazz ASH: highlights from the 2013 American Society of Haematology meeting.

The 55th annual ASH meeting was held in pleasant New Orleans and was the largest in its history, with 22,495 participants coming from 113 nations. A 'bench-to-bedside and back' attitude characterises haematology probably more than any other discipline in medicine and, as usual, this was reflected in the extremely wide breadth of the topics covered, including the last results from clinical trials and cutting-edge advancements in basic science. This year, the balance was arguably skewed: few truly clinical practice-changing results were presented. On the other hand, a great number of basic and t

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… Much better established is the role played by disruption of chromatin regulation in leukaemia and lymphoma, in particular histone methylation by components of the MLL and polycomb complexes and DNA methylation/demethylation by DNA methyltransferases and the recently characterised TET proteins [ 12 ]. …

The roles of curcumin in regulating the tumor immunosuppressive microenvironment.

Cancer is a harmful threat to human health. In addition to surgery, a variety of anticancer drugs are increasingly used in cancer therapy; however, despite the developments in multimodality treatment, the morbidity and mortality of patients with cancer patients are on the increase. The tumor-specific immunosuppressive microenvironment serves an important function in tumor tolerance and escape from immune surveillance leading to tumor progression. Therefore, identifying new drugs or foods that can enhance the tumor immune response is critical to develop improved cancer prevention methods and tr

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… Zhang et al ( 53 ) demonstrated that curcumin restores lncRNA MEG3 function in ovarian cancer cells and exosomal vesicles via demethylation, reduces the expression levels of miR-214, which can induce cell survival and cisplatin resistance through targeting the PTEN/Akt pathway ( 54 ). … The cancer-testis family is expressed on a variety of cell surfaces and hypomethylation of the cancer-testis family promoter facilitates gene expression and thus expression on the tumor cell surface; however, in contrast, demethylation of this promotor occurs in tumor cells mediating tumor immune tolerance …

Involvement of multiple myeloma cell-derived exosomes in osteoclast differentiation.

Bone disease is the most frequent complication in multiple myeloma (MM) resulting in osteolytic lesions, bone pain, hypercalcemia and renal failure. In MM bone disease the perfect balance between bone-resorbing osteoclasts (OCs) and bone-forming osteoblasts (OBs) activity is lost in favour of OCs, thus resulting in skeletal disorders. Since exosomes have been described for their functional role in cancer progression, we here investigate whether MM cell-derived exosomes may be involved in OCs differentiation. We show that MM cells produce exosomes which are actively internalized by Raw264.7 cel

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… DNA-demethylating and anti-tumor activity of synthetic miR-29b mimics in multiple myeloma. Oncotarget. 2012;3:1246–1258. doi: 10.18632/oncotarget.675. 43. … Amodio N, Bellizzi D, Leotta M, Raimondi L, Biamonte L, D'Aquila P, Di Martino MT, Calimeri T, Rossi M, Lionetti M, Leone E, Passarino G, Neri A, Giordano A, Tagliaferri P, Tassone P. miR-29b induces SOCS-1 expression by promoter demethylation and negatively regulates migration of multiple myeloma and …

Precision medicine in nasopharyngeal carcinoma: comprehensive review of past, present, and future prospect.

Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with high propensity for lymphatic spread and distant metastasis. It is prominent as an endemic malignancy in Southern China and Southeast Asia regions. Studies on NPC pathogenesis mechanism in the past decades such as through Epstein Barr Virus (EBV) infection and oncogenic molecular aberrations have explored several potential targets for therapy and diagnosis. The EBV infection introduces oncoviral proteins that consequently hyperactivate many promitotic pathways and block cell-death inducers. EBV infection is so prevalent in NPC pat

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… | Chemoresistance | Downregulation | [ 140 ] SIRT6 | Metastasis and anti-apoptosis | Upregulation | [ 141 ] | NEAT1 | Cell proliferation and anti-apoptosis | Knockout | [ 142 ] | DLC-1 | EMT | Upregulation | [ 143 ] NF-κB | RERG | Angiogenesis cytokines, colony formation, invasion and migration | Demethylation … Demethylation of ras-like estrogen-regulated growth inhibitor (RERG) has suppressed the ERK/NF-κB pathway and retarded the NPC progression by inhibiting the migration, invasion, and angiogenesis [ 144 ]. …

Spatiotemperal Dynamics of Osteoarthritis: Преобразование значений от стенда до Бедсайда.

Остеоартрит (OA) представляет собой многогранное дегенеративное совместное расстройство, вызванное различными факторами риска, такими, как возраст, механический стресс, воспаление и метаболическое воздействие. Эти элементы способствуют его разнообразным фенотипам и эндотипам, что подчеркивает имманентную сложность болезни. Участие нескольких тканей и их взаимодействие еще больше осложняет расследование ОА. Нынешние ограничения в области технологий пространственного фенотификации в сочетании со сложной сетью многофакторных взаимодействий препятствуют обнаружению надежных ранних диагностических

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… Demethylation of inflammatory genes increases their expression [ 171 ] Histone Modifications | Histone acetylation/deacetylation and methylation play key roles in OA development. | HDAC2, HDAC4: Regulate inflammation and matrix degradation [ 30 ] | Histone modifications regulate inflammatory molecules … Conversely, demethylation of promoter regions of inflammatory mediator genes leads to their increased expression [ 171 ]. Differentially methylated enhancer regions between OA patients and normal individuals have also been identified. …

The role and mechanisms of action of microRNAs in cancer drug resistance.

MicroRNAs (miRNAs) are small non-coding RNAs with a length of about 19-25 nt, which can regulate various target genes and are thus involved in the regulation of a variety of biological and pathological processes, including the formation and development of cancer. Drug resistance in cancer chemotherapy is one of the main obstacles to curing this malignant disease. Statistical data indicate that over 90% of the mortality of patients with cancer is related to drug resistance. Drug resistance of cancer chemotherapy can be caused by many mechanisms, such as decreased antitumor drug uptake, modified

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… Demethylation with 5-Aza-CdR led to reactivation of miRNA-130b expression in drug-resistant ovarian cancer cell lines, thus increasing the cell sensibility to CDDP and taxol. … A treatment of a demethylation agent, in combination with a HDAC inhibitor, could restore the expression of these miRNAs in cells [ 131 , 132 ]. …