scholarly journals Prediction of the Acute or Late Radiation Toxicity Effects in Radiotherapy Patients Using Ex Vivo Induced Biodosimetric Markers: A Review

2020 ◽  
Vol 10 (4) ◽  
pp. 285
Author(s):  
Volodymyr Vinnikov ◽  
Manoor Prakash Hande ◽  
Ruth Wilkins ◽  
Andrzej Wojcik ◽  
Eduardo Zubizarreta ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Individual Response ◽  
Lower Grade ◽  
Radiation Toxicity ◽  
Individual Level ◽  
Γh2ax Foci ◽  
Cytogenetic Testing ◽  
High Doses ◽  
Clinical Radiosensitivity ◽  
Therapeutic Irradiation

A search for effective methods for the assessment of patients’ individual response to radiation is one of the important tasks of clinical radiobiology. This review summarizes available data on the use of ex vivo cytogenetic markers, typically used for biodosimetry, for the prediction of individual clinical radiosensitivity (normal tissue toxicity, NTT) in cells of cancer patients undergoing therapeutic irradiation. In approximately 50% of the relevant reports, selected for the analysis in peer-reviewed international journals, the average ex vivo induced yield of these biodosimetric markers was higher in patients with severe reactions than in patients with a lower grade of NTT. Also, a significant correlation was sometimes found between the biodosimetric marker yield and the severity of acute or late NTT reactions at an individual level, but this observation was not unequivocally proven. A similar controversy of published results was found regarding the attempts to apply G2- and γH2AX foci assays for NTT prediction. A correlation between ex vivo cytogenetic biomarker yields and NTT occurred most frequently when chromosome aberrations (not micronuclei) were measured in lymphocytes (not fibroblasts) irradiated to relatively high doses (4–6 Gy, not 2 Gy) in patients with various grades of late (not early) radiotherapy (RT) morbidity. The limitations of existing approaches are discussed, and recommendations on the improvement of the ex vivo cytogenetic testing for NTT prediction are provided. However, the efficiency of these methods still needs to be validated in properly organized clinical trials involving large and verified patient cohorts.

In Vivo Effect of Suloctidil as an Antiplatelet Agent

1979 ◽  
Vol 41 (03) ◽  
pp. 465-474 ◽  
Author(s):  
Marcia R Stelzer ◽  
Thomas S Burns ◽  
Robert N Saunders
Keyword(s):  
Ex Vivo ◽  
Antiplatelet Agent ◽  
Ratio Method ◽  
Platelet Aggregate ◽  
Permanent Effect ◽  
Platelet Aggregates ◽  
5 Ht Uptake ◽  
High Doses

SummaryThe relationship between the effects of suloctidil in vivo as an antiplatelet agent and in vitro as a modifier of platelet serotonin (5-HT) parameters was investigated. Suloctidil was found to be effective in reducing platelet aggregates formation in the retired breeder rat as determined using the platelet aggregate ratio method (PAR) with an ED50 of 16.1 mg/kg 24 hours post administration. In contrast to the hypothesis that 5-HT depletion is involved in the anti-aggregatory mechanism of suloctidil, no correlation was found between platelet 5- HT content and this antiplatelet activity. Reduction of platelet 5-HT content required multiple injections of high doses (100 mg/kg/day) of suloctidil. Suloctidil administration for 8 days at 100 mg/kg/day, which lowered platelet 5-HT content by 50%, resulted in no permanent effect on ex vivo platelet 5-HT uptake or thrombin-induced release, nor alteration in the plasma 5-HT level. However, these platelets exhibited a short-lived, significant increase in percent leakage of 5-HT after 30 minutes of incubation. Therefore, suloctidil treatment at high doses may with time result in platelet 5-HT depletion, however this effect is probably not related to the primary anti-aggregatory activity of the drug.

Effects of Two Different Doses of Hirudin on APTT, Determined with Eight Different Reagents

1995 ◽  
Vol 73 (02) ◽  
pp. 219-222 ◽  
Author(s):  
Manuel Monreal ◽  
Luis Monreal ◽  
Rafael Ruiz de Gopegui ◽  
Yvonne Espada ◽  
Ana Maria Angles ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Anticoagulant Activity ◽  
Subcutaneous Administration ◽  
In Vitro Study ◽  
Ex Vivo Model ◽  
Suitable Candidate ◽  
Significant Prolongation ◽  
High Doses ◽  
Different Doses

SummaryThe APTT has been considered the most suitable candidate to monitor the anticoagulant activity of hirudin. However, its use is hampered by problems of standardization, which make the results heavily dependent on the responsiveness of the reagent used. Our aim was to investigate if this different responsiveness of different reagents when added in vitro is to be confirmed in an ex vivo study.Two different doses of r-hirudin (CGP 39393), 0.3 mg/kg and 1 mg/kg, were administered subcutaneously to 20 New Zealand male rabbits, and the differences in prolongation of APTT 2 and 12 h later were compared, using 8 widely used commercial reagents. All groups exhibited a significant prolongation of APTT 2 h after sc administration of hirudin, both at low and high doses. But this prolongation persisted 12 h later only when the PTTa reagent (Boehringer Mannheim) was used. In general, hirudin prolonged the APTT most with the silica- based reagents.In a further study, we compared the same APTT reagents in an in vitro study in which normal pooled plasma was mixed with increasing amount of hirudin. We failed to confirm a higher sensitivity for silica- containing reagents. Thus, we conclude that subcutaneous administration of hirudin prolongs the APTT most with the silica-based reagents, but this effect is exclusive for the ex vivo model.

scholarly journals Decrease post-transplant relapse using donor-derived expanded NK-cells

Leukemia ◽  
2021 ◽  
Author(s):  
Stefan O. Ciurea ◽  
Piyanuch Kongtim ◽  
Doris Soebbing ◽  
Prashant Trikha ◽  
Gregory Behbehani ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Ex Vivo ◽  
Disease Free Survival ◽  
Dependent Manner ◽  
Post Transplant ◽  
Haploidentical Transplantation ◽  
High Doses ◽  
High Level

AbstractIn this phase I/II clinical trial, we investigated the safety and efficacy of high doses of mb-IL21 ex vivo expanded donor-derived NK cells to decrease relapse in 25 patients with myeloid malignancies receiving haploidentical stem-cell transplantation (HSCT). Three doses of donor NK cells (1 × 105–1 × 108 cells/kg/dose) were administered on days −2, +7, and +28. Results were compared with an independent contemporaneously treated case-matched cohort of 160 patients from the CIBMTR database.After a median follow-up of 24 months, the 2-year relapse rate was 4% vs. 38% (p = 0.014), and disease-free survival (DFS) was 66% vs. 44% (p = 0.1) in the cases and controls, respectively. Only one relapse occurred in the study group, in a patient with the high level of donor-specific anti-HLA antibodies (DSA) presented before transplantation. The 2-year relapse and DFS in patients without DSA was 0% vs. 40% and 72% vs. 44%, respectively with HR for DFS in controls of 2.64 (p = 0.029). NK cells in recipient blood were increased at day +30 in a dose-dependent manner compared with historical controls, and had a proliferating, mature, highly cytotoxic, NKG2C+/KIR+ phenotype.Administration of donor-derived expanded NK cells after haploidentical transplantation was safe, associated with NK cell-dominant immune reconstitution early post-transplant, preserved T-cell reconstitution, and improved relapse and DFS. TRIAL REGISTRATION: NCT01904136 (https://clinicaltrials.gov/ct2/show/NCT01904136).

scholarly journals Multicellular ‘hotspots’ harbour high-grade potential in lower-grade gliomas

2021 ◽  
Author(s):  
Alastair J Kirby ◽  
José P Lavrador ◽  
Istvan Bodi ◽  
Francesco Vergani ◽  
Ranjeev Bhangoo ◽  
...  
Keyword(s):  
Human Brain ◽  
Brain Tissue ◽  
Aminolevulinic Acid ◽  
Ex Vivo ◽  
Brain Slices ◽  
Glioma Cells ◽  
Malignant Progression ◽  
Lower Grade ◽  
High Grade ◽  
Human Brain Tissue

Abstract Background Lower-grade gliomas may be indolent for many years before developing malignant behaviour. The reasons mechanisms underlying malignant progression remain unclear. Methods We collected blocks of live human brain tissue donated by people undergoing glioma resection. The tissue blocks extended through the peritumoral cortex and into the glioma. The living human brain tissue was cut into ex vivo brain slices and bathed in 5-aminolevulinic acid (5-ALA). High-grade glioma cells avidly take up 5-aminolevulinic acid (5-ALA) and accumulate high levels of the fluorescent metabolite, Protoporphyrin IX (PpIX). We exploited the PpIX fluorescence emitted by higher-grade glioma cells to investigate the earliest stages of malignant progression in lower-grade gliomas. Results We found sparsely-distributed ‘hot-spots’ of PpIX-positive cells in living lower-grade glioma tissue. Glioma cells and endothelial cells formed part of the PpIX hotspots. Glioma cells in PpIX hotspots were IDH1 mutant and expressed nestin suggesting they had acquired stem-like properties. Spatial analysis with 5-ALA conjugated quantum dots indicated that these glioma cells replicated adjacent to blood vessels. PpIX hotspots formed in the absence of angiogenesis. Conclusion Our data show that PpIX hotspots represent microdomains of cells with high-grade potential within lower-grade gliomas and identify locations where malignant progression could start.

scholarly journals Self-Reported Well-Being Indicators and Case Identification of Common Mental Health Disorders in Routinely Collected Health Data

2020 ◽  
Vol 5 (5) ◽  
Author(s):  
Daniel Thompson ◽  
Ann John ◽  
Richard Fry ◽  
Alan Watkins
Keyword(s):  
Mental Health ◽  
Satisfaction With Life ◽  
Well Being ◽  
Mental Health Disorders ◽  
Resource Utilisation ◽  
Individual Response ◽  
Individual Level ◽  
Case Identification ◽  
Health Disorders ◽  
Mental Well Being

IntroductionCommon mental health disorders (CMD) are significant contributors to impaired health and well-being, and drive greater health resource utilisation. Electronic health records (EHR) are increasingly used for case identification of CMD when ascertaining social determinants of mental health. We seek to compare self-reported well-being indicators in groups identified using EHR-based CMD methods. Objectives and ApproachThe National Survey for Wales (NSW) contains self-reported well-being indicators (Warwick Edinburgh Mental Well-being Scale, WEMWBS) recorded annually on ~7,000 individuals. We combined data from two NSWs and linked well-being indicators with Welsh Longitudinal General Practice (WLGP) data within the Secure Anonymised Information Linkage (SAIL) Databank, using individual response dates. We then used WGLP data to algorithmically derive identifiers of CMD cases within survey respondents. This individual-level linkage enables a comparison of NSW responses in CMD and non-CMD cases, and to assess sensitivity and specificity of the current CMD algorithm. ResultsSurvey participants comprised 18,450 adults aged 16+ and living in Wales during 16/17 or 18/19. WEMWBS responses indicate 2,338 (12.6%) participants could be considered possibly depressed, and 2,268 (12.3%) probably depressed with low mental well-being (LMW). For participants with LMW, a 42/58 percentage split is observed between male/female respondents, compared to a 45/55 respective split of those not identified with LMW. Participants with LMW recorded low measures for overall satisfaction with life, 998 (44%) reported a value of 5 or less (/10) compared to 1123 (7%) participants not identified with LMW. Similarly, 828 (37%) participants identified with LMW reported 5 or less (/10) on the life worthwhile index, compared to 800 (5%) of non-LMW participants. Conclusion / ImplicationsLinkage to the NSW provides a rich data source to compare objective well-being to algorithmically derived CMD cases from routinely collected primary care data. The individual-level linkage involved will allow for the wider determinants of mental health disorders to be examined.

scholarly journals Protection from Radiation-induced Damage in Rat’s Ileum and Colon by Combined Regimens of Melatonin and Metformin: A Histopathological Study

2020 ◽  
Vol 19 (2) ◽  
pp. 180-189 ◽  
Author(s):  
Masoud Najafi ◽  
Mohsen Cheki ◽  
Gholamreza Hassanzadeh ◽  
Peyman Amini ◽  
Dheyauldeen Shabeeb ◽  
...  
Keyword(s):  
Whole Body ◽  
Gastrointestinal Disorders ◽  
Histopathological Study ◽  
Radiation Toxicity ◽  
Pharmaceutical Treatment ◽  
Tissue Samples ◽  
Melatonin Administration ◽  
Male Wistar Rats ◽  
Radiation Induced ◽  
High Doses

Background: Radiation-induced enteritis and proctitis are common side effects of abdominopelvic cancers among patients that undergo radiotherapy for prostate, colorectal or urinary cancers. Exposure of these tissues to high doses of radiation leads to damage to villous, inflammation, pain, ulcer and bleeding, which may cause malabsorption and gastrointestinal disorders. To date, several procedures such as pharmaceutical treatment have been proposed for protection and mitigation of gastrointestinal toxicity following radiotherapy. Aims: In the current study, we aimed to investigate the possible radioprotection of ileum and colon in rats using a combination of melatonin and metformin. Methods: In this experimental study, 30 male Wistar rats were randomly assigned to six groups: control, melatonin (100 mg/kg) treatment, melatonin (100 mg/kg) plus metformin (100 mg/kg) treatment, radiation (10 Gy to whole body) group, radiation + melatonin (100 mg/kg) treatment, and radiation + melatonin (100 mg/kg) plus metformin (100 mg/kg) treatment. After 3.5 days, rats were sacrificed and their ileum and colon tissues carefully removed. Histopathological evaluations were conducted on these tissue samples. Results: Histological evaluations reported moderate to severe damages to ileum and colon following whole body irradiation. Melatonin administration was able to protect the ileum remarkably, while the combination of melatonin and metformin was less effective. Interestingly, for the colon, melatonin was less effective while its combination with metformin was able to protect against radiation toxicity completely. Conclusion: For the ileum, melatonin was a more effective radioprotector compared to its combination with metformin. However, the combination of melatonin and metformin can be proposed as an ideal radioprotector for the colon.

scholarly journals High Doses of Caffeine during the Peripubertal Period in the Rat Impair the Growth and Function of the Testis

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Minji Park ◽  
Yuri Choi ◽  
Hyeonhae Choi ◽  
Ju-Yearn Yim ◽  
Jaesook Roh
Keyword(s):  
Leydig Cells ◽  
Ex Vivo ◽  
Body Weight Gain ◽  
Male Rats ◽  
Male Rat ◽  
Control Group ◽  
High Doses ◽  
And Function ◽  
The Impact ◽  
Caffeine Exposure

Prenatal caffeine exposure adversely affects the development of the reproductive organs of male rat offspring. Thus, it is conceivable that peripubertal caffeine exposure would also influence physiologic gonadal changes and function during this critical period for sexual maturation. This study investigated the impact of high doses of caffeine on the testes of prepubertal male rats. A total of 45 immature male rats were divided randomly into three groups: a control group and 2 groups fed 120 and 180 mg/kg/day of caffeine, respectively, via the stomach for 4 weeks. Caffeine caused a significant decrease in body weight gain, accompanied by proportional decreases in lean body mass and body fat. The caffeine-fed animals had smaller and lighter testes than those of the control that were accompanied by negative influences on the histologic parameters of the testes. In addition, stimulated-testosterone ex vivo production was reduced in Leydig cells retrieved from the caffeine-fed animals. Our results demonstrate that peripubertal caffeine consumption can interfere with the maturation and function of the testis, possibly by interrupting endogenous testosterone secretion and reducing the sensitivity of Leydig cells to gonadotrophic stimulation. In addition, we confirmed that pubertal administration of caffeine reduced testis growth and altered testis histomorphology.

scholarly journals Antitumoral Effect of Laurinterol on 3D Culture of Breast Cancer Explants

Marine Drugs ◽  
2019 ◽  
Vol 17 (4) ◽  
pp. 201 ◽  
Author(s):  
Sara García-Davis ◽  
Ezequiel Viveros-Valdez ◽  
Ana Díaz-Marrero ◽  
José Fernández ◽  
Daniel Valencia-Mercado ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Crude Extract ◽  
Human Breast Cancer ◽  
Ex Vivo ◽  
3D Culture ◽  
Human Tumor ◽  
Individual Response ◽  
Human Breast ◽  
Antitumoral Effect ◽  
Wide Range

Macroalgae represent an important source of bioactive compounds with a wide range of biotechnological applications. Overall, the discovery of effective cytotoxic compounds with pharmaceutical potential is a significant challenge, mostly because they are scarce in nature or their total synthesis is not efficient, while the bioprospecting models currently used do not predict clinical responses. Given this context, we used three-dimensional (3D) cultures of human breast cancer explants to evaluate the antitumoral effect of laurinterol, the major compound of an ethanolic extract of Laurencia johnstonii. To this end, we evaluated the metabolic and histopathological effects of the crude extract of L. johnstonii and laurinterol on Vero and MCF-7 cells, in addition to breast cancer explants. We observed a dose-dependent inhibition of the metabolic activity, as well as morphologic and nuclear changes characteristic of apoptosis. On the other hand, a reduced metabolic viability and marked necrosis areas were observed in breast cancer explants incubated with the crude extract, while explants treated with laurinterol exhibited a heterogeneous response which was associated with the individual response of each human tumor sample. This study supports the cytotoxic and antitumoral effects of laurinterol in in vitro cell cultures and in ex vivo organotypic cultures of human breast cancer explants.

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