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1.
Anticancer Res ; 42(4): 1697-1706, 2022 Apr.
Article in English | MEDLINE | ID: mdl-35346988

ABSTRACT

BACKGROUND/AIM: In the age of ever-increasing developments in targeted cancer treatments, new immune-based approaches for brain tumor therapy represent an attractive avenue. Despite encouraging pre-clinical data, results in patients have been sub-optimal, likely due to tumor-induced immune suppression and intrinsic resistance to immune attack. Chemotherapy and biologic agents may be able to disrupt these mechanisms and restore tumor sensitivity to immune attack. In this study, we explore whether a combination of gemcitabine and rapamycin can sensitize medulloblastoma cells to immunotherapy in vitro and in vivo. MATERIALS AND METHODS: With the commercial medulloblastoma cell line, Daoy, we explored the concentrations of combinations of Gemcitabine with rapamycin needed to induce cytotoxicity. Next, we used flow cytometry to assess the cytotoxicity of chemotherapy-treated Daoy cells with the addition of anti-tumor T-cells, generated from naive T-cells stimulated in the presence of Daoy lysate-pulsed dendritic cells. Then, we examined the efficacy of chemotherapy alone versus chemotherapy plus immunotherapy in tumor growth inhibition of subcutaneous medulloblastoma xenografts. RESULTS: Rapamycin alone at <1,000 nM had moderate activity against Daoy cells in vitro and IC50 was >1,000 nM. Gemcitabine had a 3-day IC50 alone of 10 nM but in combination with 100 nM rapamycin, it decreased to 1 nM, suggesting increased cytotoxicity with combined therapy. Stimulated T-cells mediated in-vitro cytotoxicity, although background cytotoxicity of unstimulated "naïve" T-cells was also significant. Finally, established subcutaneous Daoy cell xenografts in SCID mice were treated with chemotherapy alone or chemotherapy plus adoptive immunotherapy (stimulated and non-stimulated). Gemcitabine and rapamycin alone significantly slowed tumor growth, but the addition of immunotherapy further augmented inhibition. CONCLUSION: Combining immunotherapy and chemo-biologic therapy inhibit medulloblastoma cell and xenograft growth, and may offer an effective treatment for patients with medulloblastoma.


Subject(s)
Brain Neoplasms , Cerebellar Neoplasms , Medulloblastoma , Animals , Brain Neoplasms/drug therapy , Cerebellar Neoplasms/drug therapy , Humans , Immunotherapy, Adoptive , Medulloblastoma/drug therapy , Medulloblastoma/metabolism , Mice , Mice, SCID
2.
Biol Blood Marrow Transplant ; 26(11): 2061-2067, 2020 11.
Article in English | MEDLINE | ID: mdl-32736008

ABSTRACT

Angiotensin II type 1 receptor activating autoantibodies (AT1R-AAs) have gained attention in solid organ transplant as non-HLA antibodies associated with rejection, vasculopathy, and graft dysfunction. These antibodies have also been reported in the context of pre-eclampsia, scleroderma, and isolated hypertension. Here, we present 3 post-hematopoietic stem cell transplant (HSCT) cases with patients demonstrating elevated levels of AT1R-AAs detected within the first year post-HSCT. All patients had hypertension, and 2 patients exhibited profound diarrhea and hypokalemia. The hypertension, in all cases, was refractory to multiple classes of antihypertensives. Upon autoantibody identification, an angiotensin receptor blocker, losartan, was promptly initiated, and all patients showed blood pressure improvement. The 2 patients with electrolyte disturbances had rapid normalization of these levels and resolution of the diarrhea. These cases demonstrate a previously unreported association of elevated AT1R-AA levels in post-HSCT patients with a rapid response to angiotensin receptor blockade initiation.


Subject(s)
Hematopoietic Stem Cell Transplantation , Hypertension , Autoantibodies , Blood Pressure , Graft Rejection , Humans , Receptor, Angiotensin, Type 1
3.
Biol Blood Marrow Transplant ; 26(10): 1819-1827, 2020 10.
Article in English | MEDLINE | ID: mdl-32653625

ABSTRACT

The pharmacokinetics of low-dose busulfan (BU) were investigated as a nonmyeloablative conditioning regimen for autologous gene therapy (GT) in pediatric subjects with adenosine deaminase-deficient severe combined immunodeficiency disease (ADA SCID). In 3 successive clinical trials, which included either γ-retroviral (γ-RV) or lentiviral (LV) vectors, subjects were conditioned with BU using different dosing nomograms. The first cohort received BU doses based on body surface area (BSA), the second cohort received doses based on actual body weight (ABW), and in the third cohort, therapeutic drug monitoring (TDM) was used to target a specific area under the concentration-time curve (AUC). Neither BSA-based nor ABW-based dosing achieved a consistent cumulative BU AUC; in contrast, TDM-based dosing led to more consistent AUC. BU clearance increased as subject age increased from birth to 18 months. However, weight and age alone were insufficient to accurately predict the dose that would consistently achieve a target AUC. Furthermore, various clinical, laboratory, and genetic factors (eg, genotypes for glutathione-S-transferase isozymes known to participate in BU metabolism) were analyzed, but no single finding predicted subjects with rapid versus slow clearance. Analysis of BU AUC and the postengraftment vector copy number (VCN) in granulocytes, a surrogate marker of the level of engrafted gene-modified hematopoietic stem and progenitor cells (HSPCs), demonstrated gene marking at levels sufficient for therapeutic benefit in the subjects who had achieved the target BU AUC. Although many factors determine the ultimate engraftment following GT, this work demonstrates that the BU AUC correlated with the eventual level of engrafted gene-modified HSPCs within a vector group (γ-RV versus LV), with significantly higher levels of granulocyte VCN in the recipients of LV-modified grafts compared to recipients of γ-RV-transduced grafts. Taken together, these findings provide insight into low-dose BU pharmacokinetics in the unique setting of autologous GT for ADA SCID, and these dosing principles may be applied to future GT trials using low-dose BU to open the bone marrow niche.


Subject(s)
Hematopoietic Stem Cell Transplantation , Severe Combined Immunodeficiency , Adenosine Deaminase/genetics , Agammaglobulinemia , Busulfan , Child , Genetic Therapy , Humans , Infant , Severe Combined Immunodeficiency/genetics , Severe Combined Immunodeficiency/therapy , Transplantation Conditioning
4.
Cancer Genet ; 239: 33-35, 2019 11.
Article in English | MEDLINE | ID: mdl-31520998

ABSTRACT

Familial adenomatous polyposis (FAP) is an autosomal dominant condition that predisposes to multiple malignancies, most commonly colorectal carcinoma, but has rarely been associated with lymphoma. We discuss one patient found to have Burkitt-like Lymphoma (BLL) with 11q aberration in the setting of previously undiagnosed FAP. We review the literature of FAP and associated malignancies and the provisional WHO classification of Burkitt-like lymphoma with 11q aberration. Both FAP and Burkitt-like lymphoma with 11q aberration involve perturbation of the MYC network and this may provide insight into a connection between these two diagnoses. However, further study is needed to elucidate if there is an increased risk of BLL and other subtypes of lymphoma among patients with FAP in order to provide optimal counseling and surveillance for patients with FAP.


Subject(s)
Adenomatous Polyposis Coli , Burkitt Lymphoma , Abdomen/diagnostic imaging , Abdomen/pathology , Adenomatous Polyposis Coli/complications , Adenomatous Polyposis Coli/diagnosis , Adenomatous Polyposis Coli/genetics , Adolescent , Burkitt Lymphoma/complications , Burkitt Lymphoma/diagnosis , Burkitt Lymphoma/genetics , Chromosome Aberrations , Humans , Male
5.
J Clin Immunol ; 37(7): 626-637, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28842866

ABSTRACT

Deficiency of adenosine deaminase (ADA, EC3.5.4.4), a housekeeping enzyme of purine metabolism encoded by the Ada gene, is a cause of human severe combined immune deficiency (SCID). Numerous deleterious mutations occurring in the ADA gene have been found in patients with profound lymphopenia (T- B- NK-), thus underscoring the importance of functional purine metabolism for the development of the immune defense. While untreated ADA SCID is a fatal disorder, there are multiple life-saving therapeutic modalities to restore ADA activity and reconstitute protective immunity, including enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) with autologous gene-corrected hematopoietic stem cells (HSC). We review the pathogenic mechanisms and clinical manifestations of ADA SCID.


Subject(s)
Adenosine Deaminase/deficiency , Adenosine Deaminase/genetics , Severe Combined Immunodeficiency/genetics , Animals , Disease Models, Animal , Humans
6.
Int J Food Sci Nutr ; 65(1): 89-96, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24020380

ABSTRACT

Alzheimer's disease (AD) is characterized by intraneuronal ß-amyloid plaques and hyperphosphorylated tau, leading to neuronal cell death and progressive memory losses. This exploratory work investigates if dietary resveratrol, previously shown to have broad anti-aging effects and improve AD pathology in vivo, leads to neuroprotective changes in specific protein targets in the mouse brain. Both wild-type and APP/PS1 mice, a transgenic AD mouse model, received control AIN-93G diet or AIN-93G supplemented with resveratrol. Pathology parameters and AD risk were assessed via measurements on plaque burden, levels of phosphorylated glycogen synthase kinase 3-ß (GSK3-ß), tau, transthyretin and drebrin. Dietary resveratrol treatment did not decrease plaque burden in APP/PS1 mice. However, resveratrol-fed mice demonstrated increases in GSK3-ß phosphorylation, a 3.8-fold increase in protein levels of transthyretin, and a 2.2-fold increase in drebrin. This study broadens our understanding of specific mechanisms and targets whereby resveratrol provides neuroprotection.


Subject(s)
Alzheimer Disease/diet therapy , Cerebrum/metabolism , Dietary Supplements , Glycogen Synthase Kinase 3/antagonists & inhibitors , Neurons/metabolism , Neuroprotective Agents/therapeutic use , Stilbenes/therapeutic use , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Cerebrum/enzymology , Cerebrum/pathology , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Humans , Male , Mice , Mice, Transgenic , Mutant Chimeric Proteins/metabolism , Mutation , Nerve Tissue Proteins/agonists , Nerve Tissue Proteins/antagonists & inhibitors , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurons/enzymology , Neurons/pathology , Neuropeptides/agonists , Neuropeptides/metabolism , Phosphorylation , Prealbumin/agonists , Prealbumin/metabolism , Presenilin-1/genetics , Presenilin-1/metabolism , Protein Processing, Post-Translational , Recombinant Proteins/metabolism , Resveratrol , Specific Pathogen-Free Organisms
7.
Article in English | MEDLINE | ID: mdl-21885269

ABSTRACT

This study determined the sensitivity of heart and brain arachidonic acid (ARA) and docosahexaenoic acid (DHA) to the dietary ARA level in a dose-response design with constant, high DHA in neonatal piglets. On day 3 of age, pigs were assigned to 1 of 6 dietary formulas varying in ARA/DHA as follows (% fatty acid, FA/FA): (A1) 0.1/1.0; (A2) 0.53/1.0; (A3-D3) 0.69/1.0; (A4) 1.1/1.0; (D2) 0.67/0.62; and (D1) 0.66/0.33. At necropsy (day 28) higher levels of dietary ARA were associated with increased heart and liver ARA, while brain ARA remained unaffected. Dietary ARA had no effect on tissue DHA accretion. Heart was particularly sensitive, with pigs in the intermediate groups having different ARA (A2, 18.6±0.7%; A3, 19.4±1.0%) and a 0.17% increase in dietary ARA resulted in a 0.84% increase in heart ARA. Further investigations are warranted to determine the clinical significance of heart ARA status in developing neonates.


Subject(s)
Arachidonic Acid/metabolism , Dietary Fats/metabolism , Docosahexaenoic Acids/metabolism , Food, Formulated , Myocardium/metabolism , Sus scrofa/metabolism , Animals , Animals, Newborn , Arachidonic Acid/administration & dosage , Brain/metabolism , Dietary Fats/administration & dosage , Docosahexaenoic Acids/administration & dosage , Fatty Acids, Unsaturated/metabolism , Linear Models , Liver/metabolism , Random Allocation , Retina/metabolism , Sus scrofa/growth & development , Tissue Distribution
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