Successful treatment and integrated genomic analysis of an infant with FIP1L1-RARA fusion-associated myeloid neoplasm

FIP1L1-RARA associated neoplasm is a very rare and aggressive disease, with only 3 previously reported cases in the literature. Herein we describe a 9-month-old boy who presented with a FIP1L1-RARA fusion associated myelodysplastic/myeloproliferative (MDS/MPN) neoplasm-like overlap syndrome, with similarities and distinct features to both acute promyelocytic leukemia (APL) and juvenile myelomonocytic leukemia (JMML). Using a combined approach of chemotherapy, differentiating agents and stem cell transplantation (allo-HCT), this patient remains in remission 20 months after allo-HCT. To our knowledge, this is only the second published pediatric case involving this condition and the only case with a favorable long-term outcome. Given the aggressive disease described in the previously published case report, as well as the successful treatment course described herein, the combinatorial use of chemotherapy, differentiation therapy, and allogeneic HCT for treatment of FIP1L1-RARA fusion associated myeloid neoplasms, should be considered.

Study of the action mechanisms of Arnica montana effects on macrophages

Objective: To test the effect of Arnica montana (Arnica m.) on human macrophages. Method: The human monocytic leukaemia cell line THP-1 was cultured and differentiated in mature macrophages with PMA and other differentiating agents. Macrophages were exposed to Arnica m. homeopathic dilutions (2c, 3c, 5c, 9c and 15c) or Control solvent. Total RNA was isolated and sequenced to perform quantitative evaluation. Results: Screening sorted out with a list of 20 genes that were significantly changed by Arnica m. 2c treatment: 7 up-regulated and 13 down-regulated. Most notably, a clearly up-regulated function concerned the proteinaceous extracellular matrix (ECM), including genes HSPG2, FBN2, FN1 (p

Fabrication of Dexamethasone-Silver Nanoparticles Entrapped Dendrimer Collagen Matrix Nanoparticles for Dental Applications

A bioengineered tooth is a well-studied subject. However, it is a challenge when seamless integration of various functionalities is required. In the case of teeth, integrating stem cell differentiating agents, regenerating the dentin tissue, and arresting the biofilm formation are three aspects that call for attention. Dental pulp stem cell differentiation to odontoblasts can be facilitated by dexamethasone (Dex). The ideal scaffold for regeneration applications – collagen (Col), has several advantages but also has no inherent rigidity. Silver nanoparticles (AgNps) are found to be an ideal material for preventing biofilm formation, with challenges arising from their stability and cytotoxicity. The route was chosen based on the successful demonstration of various platforms is the PAMAM (Den) dendrimers. The platform encompassing all the ingredients – AgNp@Den@Dex@Col had a max at 622 nm. FTIR studies revealed the presence of all components, and scaffold degradation temperature improved. A linked morphology was observed under TEM, and the zone of inhibition (MIC) was 3.5 mm, indicating good antibacterial activity. There was also a 60% reduction in biofilm formation against Staphylococcus aureus and 40% against Klebsiella pneumoniae by the fabricated nanocomposite AgNp@Den@Dex@Col. In essence, this work reports a platform where three functions of stem cell differentiation, regeneration, and biofilm formation are integrated.

Incidence of Differentiation Syndrome Associated with Treatment Regimens in Acute Myeloid Leukemia: A Systematic Review of the Literature

Differentiation syndrome (DS) is a potentially fatal adverse drug reaction caused by the so-called differentiating agents such as all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), used for remission induction in the treatment of the M3 subtype of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL). However, recent DS reports in trials of isocitrate dehydrogenase (IDH)-inhibitor drugs in patients with IDH-mutated AML have raised concerns. Given the limited knowledge of the incidence of DS with differentiating agents, we conducted a systematic literature review of clinical trials with reports of DS to provide a comprehensive overview of the medications associated with DS. In particular, we focused on the incidence of DS reported among the IDH-inhibitors, compared to existing ATRA and ATO therapies. We identified 44 published articles, encompassing 39 clinical trials, including 6949 patients. Overall, the cumulative incidence of DS across all treatment regimens was 17.7%. Incidence of DS was notably lower in trials with IDH-inhibitors (10.4%) compared to other regimens, including ATRA and/or ATO (15.4–20.6%). Compared to other therapies, the median time to onset was four times longer with IDH-inhibitors (48 vs. 11 days). Treating oncologists should be mindful of this potentially fatal adverse drug reaction, as we expect the current trials represent an underestimation of the actual incidence.

Retinoic acid/calcite micro-carriers inserted in fibrin scaffolds modulate neuronal cell differentiation

The controlled release of cell differentiating agents is crucial in many aspects of regenerative medicine. A novel scaffold based on a fibrin–calcite composite material is presented and cells are differentiated within its structure.

Neuroblastoma Cell Lines Are Refractory to Genotoxic Drug-Mediated Induction of Ligands for NK Cell-Activating Receptors

Neuroblastoma (NB), the most common extracranial solid tumor of childhood, causes death in almost 15% of children affected by cancer. Treatment of neuroblastoma is based on the combination of chemotherapy with other therapeutic interventions such as surgery, radiotherapy, use of differentiating agents, and immunotherapy. In particular, adoptive NK cell transfer is a new immune-therapeutic approach whose efficacy may be boosted by several anticancer agents able to induce the expression of ligands for NK cell-activating receptors, thus rendering cancer cells more susceptible to NK cell-mediated lysis. Here, we show that chemotherapeutic drugs commonly used for the treatment of NB such as cisplatin, topotecan, irinotecan, and etoposide are unable to induce the expression of activating ligands in a panel of NB cell lines. Consistently, cisplatin-treated NB cell lines were not more susceptible to NK cells than untreated cells. The refractoriness of NB cell lines to these drugs has been partially associated with the abnormal status of genes for ATM, ATR, Chk1, and Chk2, the major transducers of the DNA damage response (DDR), triggered by several anticancer agents and promoting different antitumor mechanisms including the expression of ligands for NK cell-activating receptors. Moreover, both the impaired production of reactive oxygen species (ROS) in some NB cell lines and the transient p53 stabilization in response to our genotoxic drugs under our experimental conditions could contribute to inefficient induction of activating ligands. These data suggest that further investigations, exploiting molecular strategies aimed to potentiate the NK cell-mediated immunotherapy of NB, are warranted.