scholarly journals Species specificity of an adrenal androgen-mediated kill-switch triggered by p53 inactivation

2017 ◽  
Vol 1 (3) ◽  
Author(s):  
Jonathan W. Nyce
Keyword(s):  
Tumor Regression ◽  
Housekeeping Gene ◽  
High Dose ◽  
Adrenal Androgen ◽  
Rac Gtpase ◽  
Natural Systems ◽  
Uncompetitive Inhibition ◽  
Switch Mechanism ◽  
High Concentrations ◽  
P53 Inactivation

Glucose-6-phosphate dehydrogenase (G6PD) is an oncoprotein that is regulated by the p53 tumor suppressor. Mutant p53 loses the ability to inhibit G6PD, and loss of G6PD control clearly plays a role in oncogenesis. The steroid hormone precursor dehydroepiandrosterone (DHEA) is an endogenous uncompetitive inhibitor of G6PD. In humans, and a few other species, the sulfated circulatory form of DHEA (DHEAS) is present at extremely high concentrations – much higher than can be accounted for by DHEA’s function as a precursor to steroid hormones. Uncompetitive inhibition is extremely rare in natural systems because it is irreversible in the presence of high concentrations of substrate and inhibitor. What has gone unappreciated is that such uncompetitive inhibition can quickly lead to cell death when the target is an obligatory housekeeping gene such as G6PD. Cells with inactivated p53 not only lose control over G6PD, but also over hexokinase (HK), the enzyme that converts glucose into glucose-6-phosphate (G6P), the substrate of G6PD. Furthermore, loss of p53 function de-represses NFκB activity, resulting in the upregulation of steroid sulfatase (SS) which converts circulating DHEAS into active DHEA. We propose that inactivation of p53 rapidly elevates G6P and DHEA concentrations in affected cells, driving uncompetitive inhibition of G6PD to lethal irreversibility. In animals with circulating DHEAS, this kill-switch mechanism may prevent most cases of p53 inactivation from becoming tumorigenic. Tumors would thus represent instances in which this mechanism had not been triggered, but which might still be triggered by application of DHEA sufficient to uncompetitively inhibit tumor G6PD. To test this hypothesis, we performed a pilot study in which dogs with cardiac hemangiosarcoma were treated with high dose (HD) DHEA supplemented with isoprene precursors to maintain geranylation of Rac GTPase. Tumor regression and longevity observed in these dogs supported the concept that some tumors retain extraordinary sensitivity to uncompetitive inhibition by DHEA.

High dose ascorbic acid treatment in COVID-19 patients raised some problems in clinical chemistry testing

2020 ◽  
Vol 45 (5) ◽  
pp. 491-498
Author(s):  
Fatih Yesildal ◽  
Ferruh Kemal Isman
Keyword(s):  
Ascorbic Acid ◽  
Ldl Cholesterol ◽  
Clinical Chemistry ◽  
Assay Method ◽  
High Dose ◽  
Serum Samples ◽  
Choice Of Treatment ◽  
High Concentrations ◽  
Clinical Chemistry Tests ◽  
Abbott Architect

AbstractObjectiveCOVID-19 pandemia still continues to threaten the whole world. High dose ascorbic acid (AA) infusion is a choice of treatment and its efficiency is still being investigated. AA interferes with many clinical chemistry tests. However, data about the interference of high concentrations of AA is not sufficient. In this study, we aimed to investigate the interference of AA at high concentrations on commonly used chemistry assays.Materials and MethodsSerum samples at AA concentrations of 200, 150, 100, 75, 50, 25, 10, 5, 2 and 0 mg/dL were prepared by using the stock solution of 15000 mg/dL AA. Each sample was analyzed by using the most common 30 chemistry tests (Abbott Architect C8000, Illinois, USA) and a POCT glucometer (STANDARD GlucoNavii, Gyeonggi-do, Republic of Korea).ResultsCreatinine, sodium and glucose (POCT) tests were found to be positively interfered by increasing AA concentrations; while direct bilirubin, lipase, UIBC, triglyceride, total cholesterol, HDL/LDL cholesterol tests were negatively interfered. Absolute interference (%) increased as the AA concentration increased.ConclusionThis is the largest and first study to investigate the interference of high dose AA, which is used in severe COVID-19 patients nowadays. Manufacturers and clinicians should be aware of the possibility of aberrant results due to high dose AA infusion. Clinicians should not forget to consult a laboratory specialist, since he is the only person to monitor the reactions in all assays, and know the technical subjects like interferences, assay method specifications. This issue is very important for correct decision-making and interpretation of the data-mining studies accurately and efficiently.

Immunomodulating functions of recombinant ovine interferon tau: potential for therapy in mulitple sclerosis and autoimmune disorders

1998 ◽  
Vol 4 (2) ◽  
pp. 63-69 ◽  
Author(s):  
O A Khan ◽  
H Jiang ◽  
P S Subramaniam ◽  
H M Johnson ◽  
S S Dhib-Jalbut
Keyword(s):  
Therapeutic Option ◽  
High Dose ◽  
Interferon Tau ◽  
Unique Type ◽  
Immune Mediated ◽  
High Concentrations ◽  
Ifn Treatment ◽  
High Doses ◽  
Mulitple Sclerosis

The interferons (IFN) are a family of complex proteins possessing antiviral, antiproliferative, and immunomodulatory activities. Two type 1 recombinant human IFN have been recently approved for the treatment of multiple sclerosis (MS). However, use of high dose type 1 IFN treatment in MS patients has been limited by dose-related toxicity. Ovine IFNt is a unique type 1 interferon discovered for its role in the animal reproductive cycle. It differs from other type 1 IFNs in that it is remarkably less toxic even at high concentrations, is able to cross species barriers, and is not inducible by viral infection. Ovine IFNt has been shown to be very effective in the treatment of animal models of MS. In this study, we examined the toxicity of OvIFNt on human T-cells at high doses and its immunregulatory properties at equivalent doses. Our experiments confirmed the remarkably non-toxic nature of OvIFNt on human cells at high concentrations as well as immunomodulating properties consistent with other type 1 IFNs including an antilymphoproliferative effect and inhibition of IFNg-induced HLA class II expression. These results suggest that OvIFNt could be developed into a potentially less toxic therapeutic option for immune-mediated disorders including MS.

Potential for Single High-Dose Influenza Immunization in Unprimed Children

PEDIATRICS ◽  
1982 ◽  
Vol 70 (6) ◽  
pp. 982-986 ◽  
Author(s):  
Peter A. Gross ◽  
Gerald V. Quinnan ◽  
Pureza F. Gaerlan ◽  
Carolyn R. Denning ◽  
Anne Davis ◽  
...  
Keyword(s):  
New York ◽  
Influenza A ◽  
Standard Dose ◽  
Geometric Mean ◽  
High Dose ◽  
York Metropolitan Area ◽  
Reaction Index ◽  
Number Of Patients ◽  
Sibling Control ◽  
High Concentrations

High concentrations of split-product vaccine (SPV) are more immunogenic than lower concentrations. These studies were verified with another influenza strain, B/Singapore/22/79. Two ether-treated SPVs were compared in 80 children and young adults. The vaccine strains were influenza A/Bangkok/79, A/Brazil/78, and B/Singapore /79; 44 patients received a high-dose SPV containing 7, 7, and 60 µg each of the respective hemagglutinins (HA) and 36 received a standard dose SPV containing 7, 7, and 7 µg of HA, respectively. Among persons initially seronegative by hemagglutination inhibition (HAI) tests, the geometric mean titer (GMT) in 15 recipients of one high dose was 97 vs GMT of 37 in 18 recipients of one standard dose (P < .05). Furthermore, 87% of high-dose recipients had HAI titer ≥ 40 vs 44% of standard dose recipients. In initially seropositive persons, GMT in 29 recipients of one high dose was 170 vs GMT of 84 in 18 recipients of one standard dose (P < .05). Immune response to the other two virus strains was comparable for the two vaccines. The reaction index for the high dose vaccine was 0.70 vs 0.45 for the standard dose (P = NS). An A/Bangkok epidemic struck the New York metropolitan area. The attack rate in unvaccinated matched sibling control subjects was 35% (15/43). There were no vaccine failures. In conclusion, in the small number of patients studied, a 60-µg HA dose of B/Singapore/79 was significantly more immunogenic than a standard 7-µg HA dose without an increase in reactogenicity.

CTIM-28. MDNA55, AN INTERLEUKIN-4 RECEPTOR TARGETED IMMUNOTHERAPY, FOR RECURRENT GBM DELIVERED BY CONVECTION ENHANCED DELIVERY (CED)

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi56-vi57
Author(s):  
John Sampson ◽  
Achal Singh Achrol ◽  
Manish K Aghi ◽  
Krystof Bankiewiecz ◽  
Martin Bexon ◽  
...  
Keyword(s):  
De Novo ◽  
Symptom Control ◽  
Recurrent Glioblastoma ◽  
Interleukin 4 ◽  
External Control ◽  
High Dose ◽  
Open Label ◽  
Convection Enhanced Delivery ◽  
High Concentrations ◽  
Dose Volumes

Abstract BACKGROUND MDNA55 is an IL4R-targeted toxin in development for treatment of recurrent glioblastoma (rGBM). MDNA55 binds to IL4R expressed by tumor cells and non-malignant cells of the tumor microenvironment. METHOD MDNA55-05 was an open-label, single-arm study of MDNA55 delivered by CED as a single treatment in patients with 1st or 2nd recurrence following de novo GBM, IDH wild type status and not indicated for resection at relapse. Dose volumes (up to 60mL) and concentration of MDNA55 (1.5 to 9.0 μg/mL) were studied. RESULTS MDNA55 showed an acceptable safety profile at all doses tested. Median OS (mOS) amongst all subjects was 11.9 months, OS-24 was 20%, and PFS-12 was 27%. Among subjects expressing high levels of IL4R (irrespective of MDNA55 dose) and low levels of IL4R expression administered high dose (≥ 180μg) of MDNA55 (IL4Rhi + IL4Rlo/hd), mOS further improved to 14.0 months with OS-24 of 20%. Unmethylated MGMT promoter status did not affect MDNA55 treatment outcomes. In the IL4Rhi + IL4Rlo/hd population (N=17), mOS was 14.9 months with OS-24 of 22%. Following treatment with high concentrations of MDNA55 (6.0 or 9.0 μg/mL), transient (median of 3 cycles) low dose Avastin (5mg/kg q2w or 7.5mg/kg q3w) was used for symptom control and steroid sparring. Among these subjects, mOS amongst all comers (N=9) and the IL4Rhi + IL4Rlo/hd group (N=8) increased to 21.8 and 18.6 months with OS-24 of 44% and 38%, respectively. CONCLUSIONS MDNA55 shows potential to benefit all rGBM patients treated at high dose irrespective of IL4R expression. In the 1:1 randomized Phase 3 trial, the study will enrol two-thirds of subjects in the SOC arm from a matched external control arm. Unlike conventional RCTs, the hybrid design sets a new precedent for GBM trials, allowing robust OS analysis while significantly reducing the number of subjects randomized to SOC arm.

scholarly journals Species-specific mechanisms of tumor suppression are fundamental drivers of vertebrate speciation: critical implications for the ‘war on cancer’

2019 ◽  
Vol 26 (2) ◽  
pp. C1-C5
Author(s):  
Jonathan W Nyce
Keyword(s):  
Tumor Suppression ◽  
De Novo ◽  
Human Cancer ◽  
Sequence Motif ◽  
Vertebrate Species ◽  
Specific Sequence ◽  
Anthropoid Primate ◽  
Uncompetitive Inhibition ◽  
High Concentrations ◽  
Suppression System

We recently reported our detection of an anthropoid primate-specific, ‘kill switch’ tumor suppression system that reached its greatest expression in humans, but that is fully functional only during the first twenty-five years of life, corresponding to the primitive human lifespan that has characterized the majority of our species' existence. This tumor suppression system is based upon the kill switch being triggered in cells in which p53 has been inactivated; such kill switch consisting of a rapid, catastrophic increase in ROS caused by the induction of irreversible uncompetitive inhibition of glucose-6- phosphate dehydrogenase (G6PD), which requires high concentrations of both inhibitor (DHEA) and G6P substrate. While high concentrations of intracellular DHEA are readily available in primates from the importation and subsequent de-sulfation of circulating DHEAS into p53-affected cells, both an anthropoid primate-specific sequence motif (GAAT) in the glucose-6-phosphatase (G6PC) promoter, and primate-specific inactivation of de novo synthesis of vitamin C by deletion of gulonolactone oxidase (GLO) were required to enable accumulation of G6P to levels sufficient to enable irreversible uncompetitive inhibition of G6PD. Malignant transformation acts as a counterforce opposing vertebrate speciation, particularly increases in body size and lifespan that enable optimized exploitation of particular niches. Unique mechanisms of tumor suppression that evolved to enable niche exploitation distinguish vertebrate species, and prevent one vertebrate species from serving as a valid model system for another. This here-to-fore unrecognized element of speciation undermines decades of cancer research data, using murine species, which presumed universal mechanisms of tumor suppression, independent of species. Despite this setback, the potential for pharmacological reconstitution of the kill switch tumor suppression system that distinguishes our species suggests that ‘normalization’ of human cancer risk, from its current 40% to the 4% of virtually all other large, long-lived species, represents a realistic near-term goal.

scholarly journals Transcriptional Regulation of Chitin Synthases by Calcineurin Controls Paradoxical Growth of Aspergillus fumigatus in Response to Caspofungin

2010 ◽  
Vol 54 (4) ◽  
pp. 1555-1563 ◽  
Author(s):  
Jarrod R. Fortwendel ◽  
Praveen R. Juvvadi ◽  
B. Zachary Perfect ◽  
Luise E. Rogg ◽  
John R. Perfect ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Molecular Mechanisms ◽  
Laboratory Strain ◽  
Chitin Synthase ◽  
High Dose ◽  
Paradoxical Effect ◽  
Paradoxical Response ◽  
Paradoxical Growth ◽  
High Concentrations ◽  
Calcineurin Signaling

ABSTRACT Attenuated activity of echinocandin antifungals at high concentrations, known as the “paradoxical effect,” is a well-established phenomenon in Candida albicans and Aspergillus fumigatus. In the yeast C. albicans, upregulation of chitin biosynthesis via the protein kinase C (PKC), high-osmolarity glycerol response (HOG), and Ca2+/calcineurin signaling pathways is an important cell wall stress response that permits growth in the presence of high concentrations of echinocandins. However, nothing is known of the molecular mechanisms regulating the mold A. fumigatus and its paradoxical response to echinocandins. Here, we show that the laboratory strain of A. fumigatus and five of seven clinical A. fumigatus isolates tested display various magnitudes of paradoxical growth in response to caspofungin. Interestingly, none of the eight strains showed paradoxical growth in the presence of micafungin or anidulafungin. Treatment of the ΔcnaA and ΔcrzA strains, harboring gene deletions of the calcineurin A subunit and the calcineurin-dependent transcription factor, respectively, with high concentrations of caspofungin revealed that the A. fumigatus paradoxical effect is calcineurin pathway dependent. Exploring a molecular role for CnaA in the compensatory chitin biosynthetic response, we found that caspofungin treatment resulted in increased chitin synthase gene expression, leading to a calcineurin-dependent increase in chitin synthase activity. Taken together, our data suggest a mechanistic role for A. fumigatus calcineurin signaling in the chitin biosynthetic response observed during paradoxical growth in the presence of high-dose caspofungin treatment.

Interleukin-2 and high-dose cisplatin in patients with metastatic melanoma: a pilot study.

1991 ◽  
Vol 9 (10) ◽  
pp. 1821-1830 ◽  
Author(s):  
P A Demchak ◽  
J W Mier ◽  
N J Robert ◽  
K O'Brien ◽  
J A Gould ◽  
...  
Keyword(s):  
Pilot Study ◽  
Metastatic Melanoma ◽  
Response Rate ◽  
Tumor Regression ◽  
Interleukin 2 ◽  
Tumor Burden ◽  
High Dose ◽  
Minor Response ◽  
Exact Test ◽  
Combined Immunotherapy

In this pilot study of metastatic melanoma, interleukin-2 (IL-2) and cisplatin (CDDP) chemotherapy were combined using an alternating schedule designed to explore potential synergism between these modalities. Bolus IL-2 was given at a dose of 600,000 IU/kg intravenously (IV) every 8 hours, days 1 to 5 and 15 to 19, followed by high-dose CDDP administered by two different regimens: (A) 135 to 150 mg/m2 IV bolus over 30 minutes with the chemoprotectant WR-2721 910 mg/m2 or (B) 50 mg/m2 IV over 2 hours every day for 3 days. The trial design allowed an assessment of response to each phase of therapy. Among 27 assessable patients, there were 10 (37%) overall responses, including three (11%) complete responses (CRs) with durations of 9, 16, and 30+ months. Tumor regression was noted in seven patients (partial response [PR], four; minor response [MR], three; response rate [RR], four of 27 [15%]) after IL-2 administration and in 14 patients (PR, 12; MR, two; RR, 12 of 27 [44%]) after CDDP treatment, demonstrating noncrossresistance between the components of the regimen. Major PRs (greater than 90% reduction of tumor burden) or CRs were only seen in patients responding to IL-2. Toxicity during IL-2 therapy was typical for high-dose IL-2 protocols and was reversible. Among the first 20 patients treated with CDDP regimen A, there were eight episodes of grade IV nephrotoxicity (creatinine level greater than 5.0 mg/dL), including three of six patients treated with an initial CDDP dose of 135 mg/m2. This side effect was more frequent among patients with liver metastasis (P less than .05, Fisher's exact test). No significant nephrotoxicity was noted in seven patients treated on regimen B. Although ototoxicity was frequent, minimal bone marrow and neurologic toxicity was noted. There were no treatment-related deaths. This combination showed at least additive activity against melanoma, and the more protracted CDDP schedule was well tolerated. This regimen may serve as a model for future combined immunotherapy and chemotherapy trials in metastatic melanoma.

scholarly journals The Influence of Cell Culture Density on the Cytotoxicity of Adipose-Derived Stem Cells Induced by L-Ascorbic Acid-2-Phosphate

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yuan-Kun Wu ◽  
Yuan-Kun Tu ◽  
Jiashing Yu ◽  
Nai-Chen Cheng
Keyword(s):  
Stem Cells ◽  
Ascorbic Acid ◽  
Cell Sheet ◽  
Metabolic Stress ◽  
Seeding Density ◽  
Cell Contact ◽  
High Dose ◽  
Adipose Derived Stem Cells ◽  
Enhanced Expression ◽  
High Concentrations

AbstractAscorbic acid-2-phosphate (A2-P) is an oxidation-resistant derivative of ascorbic acid that has been widely employed in culturing adipose-derived stem cells (ASCs) for faster expansion and cell sheet formation. While high dose ascorbic acid is known to induce cellular apoptosis via metabolic stress and genotoxic effects, potential cytotoxic effects of A2-P at high concentrations has not been explored. In this study, the relationship between ASC seeding density and A2-P-induced cytotoxicity was investigated. Spheroid-derived ASCs with smaller cellular dimensions were generated to investigate the effect of cell-cell contact on the resistance to A2-P-induced cytotoxicity. Decreased viability of ASC, fibroblast, and spheroid-derived ASC was noted at higher A2-P concentration, and it could be reverted with high seeding density. Compared to control ASCs, spheroid-derived ASCs seeded at the same density exhibited decreased viability in the A2-P-supplemented medium. The expression of antioxidant enzymes (catalase, SOD1, and SOD2) was enhanced in ASCs at higher seeding densities. However, their enhanced expression in spheroid-derived ASCs was less evident. Furthermore, we found that co-administration of catalase or N-acetylcysteine nullified the observed cytotoxicity. Collectively, A2-P can induce ASC cytotoxicity at higher concentrations, which can be prevented by seeding ASCs at high density or co-administration of another antioxidant.

scholarly journals Roles of IFN-γ in tumor progression and regression: a review

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Dragica Jorgovanovic ◽  
Mengjia Song ◽  
Liping Wang ◽  
Yi Zhang
Keyword(s):  
Immune Response ◽  
Tumor Progression ◽  
Tumor Regression ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Interferon Γ ◽  
High Dose ◽  
Main Body ◽  
Significant Research ◽  
Ifn Γ

Abstract Background Interferon-γ (IFN-γ) plays a key role in activation of cellular immunity and subsequently, stimulation of antitumor immune-response. Based on its cytostatic, pro-apoptotic and antiproliferative functions, IFN-γ is considered potentially useful for adjuvant immunotherapy for different types of cancer. Moreover, it IFN-γ may inhibit angiogenesis in tumor tissue, induce regulatory T-cell apoptosis, and/or stimulate the activity of M1 proinflammatory macrophages to overcome tumor progression. However, the current understanding of the roles of IFN-γ in the tumor microenvironment (TME) may be misleading in terms of its clinical application. Main body Some researchers believe it has anti-tumorigenic properties, while others suggest that it contributes to tumor growth and progression. In our recent work, we have shown that concentration of IFN-γ in the TME determines its function. Further, it was reported that tumors treated with low-dose IFN-γ acquired metastatic properties while those infused with high dose led to tumor regression. Pro-tumorigenic role may be described through IFN-γ signaling insensitivity, downregulation of major histocompatibility complexes, upregulation of indoleamine 2,3-dioxygenase, and checkpoint inhibitors such as programmed cell death ligand 1. Conclusion Significant research efforts are required to decipher IFN-γ-dependent pro- and anti-tumorigenic effects. This review discusses the current knowledge concerning the roles of IFN-γ in the TME as a part of the complex immune response to cancer and highlights the importance of identifying IFN-γ responsive patients to improve their sensitivity to immuno-therapies.

scholarly journals 2'-Deoxycytidine protects normal human bone marrow progenitor cells in vitro against the cytotoxicity of 3'-azido-3'-deoxythymidine with preservation of antiretroviral activity

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 1923-1928 ◽  
Author(s):  
K Bhalla ◽  
M Birkhofer ◽  
GR Li ◽  
S Grant ◽  
W MacLaughlin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
High Dose ◽  
Normal Bone Marrow ◽  
Normal Bone ◽  
Bone Marrow Progenitor Cells ◽  
Bone Marrow Progenitor ◽  
High Concentrations ◽  
Anti Hiv

Abstract Bone marrow cytotoxicity of 3′-azido-3′-deoxythymidine (AZT), an anti- human immunodeficiency virus (anti-HIV) drug, has been attributed to deoxyribonucleotide pool perturbations that might result in impaired DNA synthesis in normal bone marrow elements. We examined, in vitro, the effect of high, but clinically achievable and nontoxic, concentrations of 2′-deoxycytidine (dCyd) (greater than or equal to 100 mumol/L) on high-dose AZT mediated growth inhibition and intracellular biochemical perturbations in normal bone marrow progenitor cells. Colony formation by bone marrow progenitor cells in semisolid medium was significantly protected by dCyd against the inhibitory effects of co-administered, high concentrations of AZT (10 mumol/L). Also, dCyd significantly corrected AZT mediated depletion of intracellular thymidine triphosphate (dTTP) and dCyd triphosphate (dCTP) levels in normal bone marrow mononuclear cells (BMMC). Moreover, dCyd reduced the intracellular accumulation of AZT triphosphate (AZT-TP) and its DNA incorporation in BMMC. In contrast, co-administration of dCyd (100 mumol/L to 1 mmol/L) did not reverse AZT (10 mumol/L) mediated suppression of HIV infectivity in HUT-102 cells in culture, although a partial reduction in intracellular AZT-TP pools and its DNA incorporation as well as a correction of AZT mediated depletion of dTTP and dCTP pools was observed in these cells. These studies suggest that dCyd at high concentrations might ameliorate the bone marrow cytotoxicity of high-dose AZT without impairing its anti-HIV effect.

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