- IGFBP7 Induces Differentiation and Loss of Survival of Human Acute Myeloid Leukemia Stem Cells without Affecting Normal Hematopoiesis. [Journal Article]
- CRCell Rep 2018 Dec 11; 25(11):3021-3035.e5
- Leukemic stem cells (LSCs) are thought to be the major cause of the recurrence of acute myeloid leukemia (AML) due to their potential for self-renewal. To identify therapeutic strategies targeting LS...
Leukemic stem cells (LSCs) are thought to be the major cause of the recurrence of acute myeloid leukemia (AML) due to their potential for self-renewal. To identify therapeutic strategies targeting LSCs, while sparing healthy hematopoietic stem cells (HSCs), we performed gene expression profiling of LSCs, HSCs, and leukemic progenitors all residing within the same AML bone marrow and identified insulin-like growth factor-binding protein 7 (IGFBP7) as differentially expressed. Low IGFBP7 is a feature of LSCs and is associated with reduced chemotherapy sensitivity. Enhancing IGFBP7 by overexpression or addition of recombinant human IGFBP7 (rhIGFBP7) resulted in differentiation, inhibition of cell survival, and increased chemotherapy sensitivity of primary AML cells. Adding rhIGFBP7 reduced leukemic stem and/or progenitor survival and reversed a stem-like gene signature, but it had no influence on normal hematopoietic stem cell survival. Our data suggest a potential clinical utility of the addition of rhIGFBP7 to current chemotherapy regimens to decrease AML relapse rates.
- Risk of bleeding after ultrasound-guided jugular central venous catheter insertion in severely thrombocytopenic oncologic patients. [Journal Article]
- AJAm J Surg 2019; 217(1):133-137
- CONCLUSIONS: Incidence of minor bleeding is low in severely thrombocytopenic patients after USGIJ catheter insertion. Prophylactic platelet transfusion may be reserved for patients with identified risk factors.
- Generation of Suicide Gene-Modified Chimeric Antigen Receptor-Redirected T-Cells for Cancer Immunotherapy. [Journal Article]
- MMMethods Mol Biol 2019; 1895:57-73
- Chimeric antigen receptor (CAR)-redirected T-cells are a powerful tool for the treatment of several type of cancers; however, they can cause several adverse effects including cytokine release syndrom...
Chimeric antigen receptor (CAR)-redirected T-cells are a powerful tool for the treatment of several type of cancers; however, they can cause several adverse effects including cytokine release syndrome, off-target effects resulting in potentially fatal organ damage or even death. Particularly, for CAR T-cells redirected toward acute myeloid leukemia (AML) antigens myelosuppression can be a challenge. The previously validated inducible Caspase9 (iC9) suicide gene system is one of the approaches to control the infused cells in vivo through its activation with a nontherapeutic chemical inducer of dimerizer (CID). We performed a preclinical validation using a model of CD33+ AML, and generated iC9 CAR T-cells co-expressing a CAR targeting the AML-associated antigen CD33 and a selectable marker (ΔCD19). ΔCD19 selected (sel.) iC9-CAR.CD33 T-cells were effective in controlling leukemia growth in vitro, and could be partially eliminated (76%) using a chemical inducer of dimerization that activates iC9. Moreover, to completely eliminate residual cells, a second targeted agent was added. Future plans with these methods are to investigate the utility of iC9-CAR.CD33 T-cells as part of the conditioning therapy for an allogeneic hematopoietic stem cell transplant. Additional strategies that we are currently validating include (1) the modulation of the suicide gene activation, using different concentrations of the inducing agent(s), to be able to eliminate CAR T-cells modified by a regulatable gene, ideally aiming at preserving a proportion of the infused cells (and their antitumor activity) for mild to moderate toxicities, or (2) the co-expression of an inhibitory CAR aiming at sparing normal cells co-expressing an antigen not shared with the tumor.
- Update on Immunotherapy in AML and MDS: Monoclonal Antibodies and Checkpoint Inhibitors Paving the Road for Clinical Practice. [Journal Article]
- AEAdv Exp Med Biol 2018; 995:97-116
- In the past few years, our improved understanding of the pathogenesis of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) has led to remarkable advances in the development of novel the...
In the past few years, our improved understanding of the pathogenesis of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) has led to remarkable advances in the development of novel therapeutic approaches for these diseases. This chapter summarizes the available clinical data with immune-based therapeutic modalities in AML and MDS, focusing on monoclonal antibodies, T cell engager antibodies, chimeric antigen receptor (CAR)-T cells, and checkpoint blockade via blockade of PD-1/PD-L1 or CTLA4. Numerous clinical trials are currently ongoing in patients with AML and MDS, both in the frontline and relapsed refractory setting. Given the natural diversity of AML blasts, it became apparent that the best responses would be achieved with rationally designed combination strategies of immune therapy, molecular therapy, and chemotherapy. A number of such combinations are enrolling patients with AML in various clinical settings. Biomarkers to select the optimal combination regimen for individual patients are critical.
- Alteration of gene expression profile in CD3+ T-cells after downregulating MALT1. [Journal Article]
- ITImmunotargets Ther 2018; 7:77-81
- CONCLUSIONS: MALT1 suppression may contribute to immunodeficiency in T cells via suppression of T cell activation and proliferation pathways. These data may help to explain some of the characteristics of immunodeficiency of T cells.
- Camalexin Induces Apoptosis via the ROS-ER Stress-Mitochondrial Apoptosis Pathway in AML Cells. [Journal Article]
- OMOxid Med Cell Longev 2018; 2018:7426950
- Camalexin is a phytoalexin that accumulates in various cruciferous plants upon exposure to environmental stress and plant pathogens. It was shown that camalexin has potent antitumor properties, but i...
Camalexin is a phytoalexin that accumulates in various cruciferous plants upon exposure to environmental stress and plant pathogens. It was shown that camalexin has potent antitumor properties, but its underlying mechanisms are still elusive. In the present study, we evaluated the effects of camalexin on human leukemic cells and normal polymorph nuclear cells. CCK-8 assay was used to determine cell viability after camalexin treatment. Apoptosis, intracellular reactive oxygen species (ROS) levels, and loss of mitochondrial membrane potential (MMP) were measured by flow cytometry. The activity of SOD, catalase, and ratio of GSH/GSSG were assayed. ER stress and apoptotic signaling pathway was examined by Western blot. Xenograft mice were used to verify the effect of camalexin in vivo. Our results indicated that camalexin inhibited viability of leukemic but not normal polymorph nuclear cells. Furthermore, camalexin induces apoptosis via the mitochondrial pathway in a caspase-dependent manner. We also observed ER stress is located upstream of apoptosis induced by camalexin. Besides, ROS levels, SOD activity, CAT activity, and GSSG levels were significantly enhanced while the GSH level was decreased after treatment of camalexin. In addition, the generation of ROS is critical for the ER stress and apoptosis induced by camalexin. Finally, administration of camalexin suppresses xenograft tumor graft growth without obvious toxicity. Taken together, this study indicates that camalexin exerts antitumor effects against leukemia cells via the ROS-ER stress-mitochondrial apoptosis pathway.
- The return of gemtuzumab ozogamicin: a humanized anti-CD33 monoclonal antibody-drug conjugate for the treatment of newly diagnosed acute myeloid leukemia. [Review]
- OTOnco Targets Ther 2018; 11:8265-8272
- Through the years gemtuzumab ozogamicin (GO) has moved from a panacea in the treatment of acute myeloid leukemia (AML) to a pariah and back again. Early promise of targeted therapy with accelerated a...
Through the years gemtuzumab ozogamicin (GO) has moved from a panacea in the treatment of acute myeloid leukemia (AML) to a pariah and back again. Early promise of targeted therapy with accelerated approval in the United States in 2000 gave way to fear over increased toxicity in the absence of efficacy, which subsequently resulted in the drug manufacturer voluntarily withdrawing GO from the market in 2010. We outline the history of GO in terms of initial drug development and early clinical trials that ultimately led the way to GO frontline use in AML based on a series of Phase III studies. Among these studies, we discuss the similarities and differences in terms of dosing, frequency, response rates, and toxicities that ultimately led to the re-approval of GO in 2017 based on efficacy, particularly in patients with core-binding factor (CBF) leukemia. Herein, we also review the clinical efficacy of GO in the frontline treatment of acute promyelocytic leukemia, which is based on either initial patient high-risk disease or potential co-morbidities that preclude the use of arsenic trioxide (ATO). Finally, we assess the current evidence for biomarkers aside from initial cytogenetics that may predict a favorable response to GO.
- Age-specific biological and molecular profiling distinguishes paediatric from adult acute myeloid leukaemias. [Journal Article]
- NCNat Commun 2018 Dec 11; 9(1):5280
- Acute myeloid leukaemia (AML) affects children and adults of all ages. AML remains one of the major causes of death in children with cancer and for children with AML relapse is the most common cause ...
Acute myeloid leukaemia (AML) affects children and adults of all ages. AML remains one of the major causes of death in children with cancer and for children with AML relapse is the most common cause of death. Here, by modelling AML in vivo we demonstrate that AML is discriminated by the age of the cell of origin. Young cells give rise to myeloid, lymphoid or mixed phenotype acute leukaemia, whereas adult cells give rise exclusively to AML, with a shorter latency. Unlike adult, young AML cells do not remodel the bone marrow stroma. Transcriptional analysis distinguishes young AML by the upregulation of immune pathways. Analysis of human paediatric AML samples recapitulates a paediatric immune cell interaction gene signature, highlighting two genes, RGS10 and FAM26F as prognostically significant. This work advances our understanding of paediatric AML biology, and provides murine models that offer the potential for developing paediatric specific therapeutic strategies.
- Left ventricular outflow tract obstruction with abnormal papillary muscles. [Journal Article]
- JCJ Cardiol Cases 2015; 11(2):69-72
- A 65-year-old man with a history of hypertension was admitted to our hospital with fainting and syncope. He had experienced recurrent syncope since 20 years of age. On admission, systolic heart murmu...
A 65-year-old man with a history of hypertension was admitted to our hospital with fainting and syncope. He had experienced recurrent syncope since 20 years of age. On admission, systolic heart murmur was audible at the apex of the heart. Echocardiography revealed anteriorly displaced papillary muscles (PMs), elongation of the anterior mitral valve leaflet (AML), and systolic anterior motion (SAM) of the AML. Color Doppler imaging showed accelerated flow with a pressure gradient (PG) of 56 mmHg at the left ventricular outflow tract (LVOT). Cardiac magnetic resonance imaging revealed mild asymmetric septal hypertrophy and multiple accessory PMs. Cine images clearly demonstrated SAM and LVOT obstruction due to anteriorly displaced PMs. Based on these findings, the patient was diagnosed as having hypertrophic cardiomyopathy and LVOT obstruction due to abnormal PMs. Oral administration of bisoprolol (2.5 mg/day) was initiated, because the patient rejected surgical treatment. Follow-up echocardiography revealed a gradual decrease in the LVOT-PG to 24 mmHg, and no episodes of fainting or syncope have recurred for 2 years after the initiation of bisoprolol. <Learning objective: Abnormal papillary muscle (PM) is an unusual cause of left ventricular outflow tract (LVOT) obstruction, and cardiac magnetic resonance (CMR) imaging has been reported to be useful for diagnosis of abnormal PM. Abnormal PMs with LVOT obstruction are usually treated by surgical correction, and therefore, reports on medical treatment are limited. We report a case of LVOT obstruction due to abnormal PMs, which was accurately diagnosed by CMR imaging and successfully treated with a beta-blocker.>.
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- Population Pharmacokinetic Analysis of Decitabine in Pediatric Patients With Acute Myeloid Leukemia. [Journal Article]
- JCJ Clin Pharmacol 2018 Dec 11
- Dacogen, the formulated product of the pharmaceutically active agent decitabine (5 aza-2'-deoxycytidine), is approved for treatment of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML...
Dacogen, the formulated product of the pharmaceutically active agent decitabine (5 aza-2'-deoxycytidine), is approved for treatment of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML). The current analysis was performed to characterize the pharmacokinetics of decitabine in pediatric patients with AML and evaluate their consistency with the PK in adult patients. A population pharmacokinetic model was developed by pooling decitabine concentration-time data from 5 adult (AML and MDS) and 2 pediatric (AML) studies. A total of 840 concentration-time data points obtained from 71 adults and 28 pediatric subjects (1 to 16 years old) were available for analysis. A 2-compartment linear pharmacokinetic (PK) model with allometric scaling using body surface area accounting for body size adequately described the PK of decitabine. After accounting for body size, decitabine pharmacokinetics were not affected by age, sex, race, dosing regimen, renal function (creatinine clearance), bilirubin, or disease type (AML or MDS) and all PK parameters (including clearance, steady-state volume of distribution, maximum concentration, time to reach maximal concentration, and terminal half-life) were comparable between adult and pediatric patients. Simulated concentration-time profiles using the final population PK model suggested that decitabine exposure at steady state was similar in adults and pediatrics for a 20 mg/m2 decitabine dose administered as a 1-hour infusion once daily. The current analysis suggests that decitabine PK is similar in pediatric AML patients and a combined adult AML and MDS population.