scholarly journals A Model of Chemotherapy-Induced Tumor Dormancy: Doxorubicin Retention and Degradation Defines Resumed Growth in Vivo

2021 ◽  
Author(s):  
Gintaras Zaleskis ◽  
Sima Garberytė ◽  
Božena Pavliukevičienė ◽  
Dainius Characiejus ◽  
Karolina Žilionytė ◽  
...  
Keyword(s):  
Tumor Cells ◽  
High Performance ◽  
Survival Rates ◽  
Cancer Recurrence ◽  
Cytotoxic Drug ◽  
Dormant Cells ◽  
Viable Cells ◽  
One Year ◽  
The Relationship

Abstract Background. Cancer recurrence after adjuvant chemotherapy with long periods of remission is common. After cessation of the therapy, the dormant cells may repopulate, but the signals that control the tumor to exit dormancy are not completely understood. We hypothesized that tissue bound cytotoxic drug indwelling in a body for years might somehow contribute to dormancy or recurrence of a tumor. The purpose of this study was to design a model demonstrating that viable cells implanted in mice can repopulate or be suppressed, depending on the cytotoxic preload conditions.Methods. A two-step dormancy/recurrence (TSDR) murine model was designed, which mimics the extrusion of taken up drug from tumor cells. The viable cells preloaded with drug were implanted into mice. The survival rates of these mice were then used as criteria to demonstrate the relationship between resumed growth and drug cellular efflux/viability. The drug internalization patterns following their exposure to doxorubicin (dox) or degraded dox (dox-dgr) were investigated by exploring flow cytometry, spectral analysis, high performance liquid chromatography and confocal microscopy. Antiproliferative and myelotoxic capacity was evaluated by hematological nadir induced by the iv injected drug. Results. The viable SL2 lymphoma cells exposed to 10 µg/ml of dox for 30 min and injected into syngeneic DBA/2 mice were made unable to recure. Exposure of cells to lower dox concentrations (0.01 – 1.0 µg/ml) resulted in tumor recurrence, similar to that which was observed during implantation of an untreated tumor. Dox-dgr kept at 37 °C for 365 days lost its tumoricidal and antiproliferative capacity and displayed a loss of selectivity of nuclear fluorescence.Conclusions. Our TSDR model is a rapid convenient tool to study in vivo behavior of cells preloaded with cytotoxic drug. This approach focuses on mechanisms of tumor cells exiting dormancy, in relation to cytotoxic drug efflux. Multiple modifications of our TSDR model are possible, including nude mice models. As an example, we used one-year body temperature exposed dox to demonstrate its inability to retain sufficient cytotoxic capacity.

scholarly journals Roles of OX40 and OX40 Ligand in Mycosis Fungoides and Sézary Syndrome

2021 ◽  
Vol 22 (22) ◽  
pp. 12576
Author(s):  
Yuki Kawana ◽  
Hiraku Suga ◽  
Hiroaki Kamijo ◽  
Tomomitsu Miyagaki ◽  
Makoto Sugaya ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Mycosis Fungoides ◽  
Cell Lines ◽  
Survival Rates ◽  
Clinical Samples ◽  
Sézary Syndrome ◽  
Sezary Syndrome ◽  
And Function

Mycosis fungoides (MF) and Sézary syndrome (SS), the most common types of cutaneous T-cell lymphoma (CTCL), are characterized by proliferation of mature CD4+ T-helper cells. Patients with advanced-stage MF and SS have poor prognosis, with 5-year survival rates of 52%. Although a variety of systemic therapies are currently available, there are no curative options for such patients except for stem cell transplantation, and thus the treatment of advanced MF and SS still remains challenging. Therefore, elucidation of the pathophysiology of MF/SS and development of medical treatments are desired. In this study, we focused on a molecule called OX40. We examined OX40 and OX40L expression and function using clinical samples of MF and SS and CTCL cell lines. OX40 and OX40L were co-expressed on tumor cells of MF and SS. OX40 and OX40L expression was increased and correlated with disease severity markers in MF/SS patients. Anti-OX40 antibody and anti-OX40L antibody suppressed the proliferation of CTCL cell lines both in vitro and in vivo. These results suggest that OX40–OX40L interactions could contribute to the proliferation of MF/SS tumor cells and that the disruption of OX40–OX40L interactions could become a new therapeutic strategy for the treatment of MF/SS.

scholarly journals In Vitro Glioblastoma Models: A Journey into the Third Dimension

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2449
Author(s):  
Mayra Paolillo ◽  
Sergio Comincini ◽  
Sergio Schinelli
Keyword(s):  
Tumor Cells ◽  
Single Cell Analysis ◽  
3D Models ◽  
Primary Brain Tumor ◽  
Molecular Features ◽  
Third Dimension ◽  
One Year ◽  
The Impact

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults, with an average survival time of about one year from initial diagnosis. In the attempt to overcome the complexity and drawbacks associated with in vivo GBM models, together with the need of developing systems dedicated to screen new potential drugs, considerable efforts have been devoted to the implementation of reliable and affordable in vitro GBM models. Recent findings on GBM molecular features, revealing a high heterogeneity between GBM cells and also between other non-tumor cells belonging to the tumoral niche, have stressed the limitations of the classical 2D cell culture systems. Recently, several novel and innovative 3D cell cultures models for GBM have been proposed and implemented. In this review, we first describe the different populations and their functional role of GBM and niche non-tumor cells that could be used in 3D models. An overview of the current available 3D in vitro systems for modeling GBM, together with their major weaknesses and strengths, is presented. Lastly, we discuss the impact of groundbreaking technologies, such as bioprinting and multi-omics single cell analysis, on the future implementation of 3D in vitro GBM models.

Single Cell RNA Sequencing Reveals Increased Adhesion Signals in Treatment-Resistant Tumor Stem Cells in a Preclinical Mouse Model of Genetically Engineered Patient-Derived Acute Lymphoblastic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2630-2630
Author(s):  
Ebinger Sarah ◽  
Özdemir Erbey ◽  
Sebastian Tiedt ◽  
Christoph Ziegenhain ◽  
Catarina Castro Alves ◽  
...  
Keyword(s):  
Stem Cells ◽  
High Risk ◽  
Tumor Cells ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Drug Resistant ◽  
Treatment Resistant ◽  
Dormant Cells ◽  
Resistant Cells

Abstract Treatment-resistant cells determine prognosis and outcome of cancer patients as they induce relapse with poor outcome. Novel therapeutic options are urgently needed to eradicate chemo-resistant tumor cells. Towards this aim, a deep understanding is required on mechanisms determining treatment-resistance in vivo and the ability to induce relapse. Here, we aimed to identify and characterize the challenging rare subpopulation of drug resistant cells which survive in vivo chemo-therapy and are able to induce relapse. As technical approach, we used the individualized mouse model of acute lymphoblastic leukemia (ALL) and amplified primary tumor cells in mice to generate patient-derived xenograft (PDX) cells. Upon genetic engineering by lentiviral transduction, PDX ALL cells expressed the three transgenes NGFR, a red fluorochrome and luciferase. While recombinant luciferase was used for in vivo imaging, a combined MACS/FACS procedure based on the expression of the transgenes enabled enriching PDX ALL cells from murine bone marrow by a factor above 10,000. Staining of PDX cells with CFSE was used to discriminate between highly proliferative and dormant tumor cells in vivo. We treated mice harboring triple-transgenic, CFSE labeled PDX ALL cells with conventional chemotherapy; while in vivo treatment decreased the number of highly proliferative cells by more than 1 order of magnitude, the amount of dormant cells remained completely unchanged. Isolated, drug resistant cells revealed leukemia propagating potential and induced leukemia upon transplantation into next generation mice. Thus and using dormancy as an anchor, we could identify, isolate and enrich a subpopulation of treatment-resistant PDX ALL cells which might mimic relapse-inducing cells at minimal residual disease in patients. We next aimed at characterizing the expression profile of these cells and were able to isolate single cells out of the low number of dormant cells to perform single cell RNA sequencing. Dormant, drug-resistant cells showed increased expression of several adhesion molecules suggesting an increased dependence on the bone marrow environment. Upon using gene set enrichment analyses, drug-resistant cells showed a highly similar expression profile to primary high risk leukemia subpopulations such as primary high risk ALL cells, the subpopulation of CD34 positive CML cells and leukemic or benign hematopoietic stem cells. Taken together, treatment-resistant PDX ALL stem cells isolated and enriched from mice showed increased expression of adhesion molecules and resemble primary tumor cells of high risk subpopulations. These cells represent valuable tools to increase our understanding of mechanisms in minimal residual disease and relapse in patients. Our model will help to develop novel therapies which eliminate treatment resistant cells, prevent disease relapse and increase the prognosis of patients with ALL. Disclosures No relevant conflicts of interest to declare.

Clinical validation of a medical device for in vivo isolation of circulating tumor cells in prostate cancer patients: One-year follow-up.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. e16027-e16027 ◽  
Author(s):  
Gerit Theil ◽  
Kersten Fischer ◽  
Thomas Krahn ◽  
Andre Schumann ◽  
Kathrin Haubold ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Medical Device ◽  
Circulating Tumor Cells ◽  
Clinical Validation ◽  
One Year

scholarly journals SCREENING ANTIBACTERIAL EFFECTS OF VIETNAMESE PLANT EXTRACTS AGAINST PATHOGENS CAUSED ACUTE HEPATOPANCREATIC NECROSIS DISEASE IN SHRIMPS

2018 ◽  
Vol 11 (5) ◽  
pp. 77 ◽  
Author(s):  
Hai Thanh Nguyen ◽  
Lua Thi Dang ◽  
Hanh Thi Nguyen ◽  
Hai Ha Hoang ◽  
Ha Thi Ngoc Lai ◽  
...  
Keyword(s):  
High Performance ◽  
Pathogenic Bacteria ◽  
Survival Rates ◽  
Antibacterial Properties ◽  
Piper Betle ◽  
Antibacterial Effects ◽  
Plant Materials ◽  
Acute Hepatopancreatic Necrosis Disease

Objectives: The objectives are aimed to investigate the antibacterial properties of five Vietnamese medicinal plants against acute hepatopancreatic necrosis disease (AHPND)-caused bacterial pathogens, to verify their potentials to apply as a new treatment therapy.Methods: Extracts from plants, such as Psidium guajava leaf, Piper betle L. leaf, Phyllanthus amarus leaf, Rhodomyrtus tomentosa seed, and Allium sativum bulb, were tested against three AHPND-caused bacteria. Agar infusion and broth dilution methods were employed to evaluate extract in vitro antibacterial effects, while experiments with cultured whiteleg shrimps were applied to access their safety when applied in vivo. High-performance liquid chromatography (HPLC) analysis was applied to identify components in the extracts.Results: P. amanus and R. tomentosa extracts exerted the strongest inhibition on tested bacteria. Other extracts, including P. betel and P. guajava, were less effective, while A. sativum showed no effects against bacteria. In safety assessment experiments, we observed that only crude extracts of R. tomentosa and A. satium were safe, while others significantly reduced their survival rates. HPLC showed that extracts of high antibacterial properties had rich phenol constituents. In addition, the phenolic profile of R. tomentosa showed the presence of piceatannol.Conclusion: Considering both of antibacterial effects and safety properties altogether, we concluded that among the five examined plant materials of this study, R. tomentosa had the highest potential to apply in AHPND treatment, as only this plant showed the high effects on pathogenic bacteria while were still safe for host aquatic shrimps.

Studies on the Relationship between 67Ga-Citrate Accumulation and Calcium Metabolism in Tumor Cells

1973 ◽  
Vol 12 (03) ◽  
pp. 240-251
Author(s):  
Leopoldo Anghileri
Keyword(s):  
Tumor Cells ◽  
Calcium Metabolism ◽  
Ghost Cells ◽  
Citrate Accumulation ◽  
The Relationship ◽  
67Ga Citrate

L’incorporation in vivo du citrate de gallium (67Ga) et du chlorure de calcium (45Ca) dans les cellules de la tumeur ascitique d’Ehrlich a été étudiée par la technique des “ghost cells”. Les résultats indiquent qu’à peu près 50% du 67Ga intracellulaire est incorporé par le matérial cellulaire résiduel qui ist formé principalement par des phospholipides, protéines et acides nucléiques. La relation existant entre les deux incorporations (du 67Ga et du 45Ca) est discutée.

Survival and in vivo adhesion of human isolates Lactobacillus gasseri LF221 and K7 in weaned piglets and their effects on coliforms, clostridia and lactobacilli viable counts in faeces and mucosa

2006 ◽  
Vol 73 (4) ◽  
pp. 417-422 ◽  
Author(s):  
Bojana Bogovič Matijašić ◽  
Saša Stojković ◽  
Irena Rogelj
Keyword(s):  
Intestinal Mucosa ◽  
Survival Rates ◽  
Weaned Piglets ◽  
Ileal Mucosa ◽  
Lactobacillus Gasseri ◽  
Viable Cells ◽  
Probiotic Treatment ◽  
Individual Strain ◽  
Probiotic Strains

In in vivo study on 24 weaned piglets (8 per group), the survival rates of human isolates Lactobacillus gasseri K7 and LF221 were quantified by selective enumeration on MRS agar with rifampicin, and the presence of both strains in intestinal mucosa was examined. Faeces from individual animals were analysed for the number (cfu/g) of coliforms, lactobacilli, clostridia and both of the two probiotic strains during 2-weeks probiotic application period (5×1010 cfu of individual strain/day) and 1 week after the probiotic treatment was ceased. Samples of duodenum, jejunum and ileum of sacrificed animals (5th or 20th day) were also examined microbiologically. A great variability in the microflora of faeces and mucosa was observed even between equally treated animals. The survival of both Lb. gasseri strains was established by their detection in the faeces (2·5×105 to 3·3×105 cfu of K7 strain/g faeces; 4·5×105 to 5×105 cfu of LF221 strain/g). In two animals, the LF221 or K7 viable cells were found in the faeces 6 d after ceasing probiotic application. In both animals from the group fed with Lb. gasseri K7 that were sacrificed 5 d after weaning, the presence of K7 strain was found either in the mucosa of duodenum (140 cfu/10 cm2) and jejunum (170 cfu/10 cm2) or in the ileum (1600 cfu/10 cm2). LF221 cells were detected in the ileal mucosa of one piglet (820 cfu/10 cm2). The results demonstrated the capability of both tested strains of in vivo adhesion to intestinal mucosa and of temporary colonisation of the piglets' intestine.

Ultrastructural Correlations between Clonal Human Tumor Colonies and in Vivo Neoplasms

1982 ◽  
Vol 40 ◽  
pp. 210-211
Author(s):  
M.J. Murphy ◽  
R.R. Price ◽  
J.C. Sloman
Keyword(s):  
Cultured Cells ◽  
Human Tumor ◽  
Cell Type ◽  
Tumor Mass ◽  
Initial Cell ◽  
Cloning Assay ◽  
Human Tumor Cloning ◽  
The Relationship

The in vitro human tumor cloning assay originally described by Salmon and Hamburger has been applied recently to the investigation of differential anti-tumor drug sensitivities over a broad range of human neoplasms. A major problem in the acceptance of this technique has been the question of the relationship between the cultured cells and the original patient tumor, i.e., whether the colonies that develop derive from the neoplasm or from some other cell type within the initial cell population. A study of the ultrastructural morphology of the cultured cells vs. patient tumor has therefore been undertaken to resolve this question. Direct correlation was assured by division of a common tumor mass at surgical resection, one biopsy being fixed for TEM studies, the second being rapidly transported to the laboratory for culture.

Osseointegration interface of calcified bone and endosseous implants

1992 ◽  
Vol 50 (2) ◽  
pp. 1096-1097
Author(s):  
K.E. Krizan ◽  
J.E. Laffoon ◽  
M.J. Buckley
Keyword(s):  
Structure And Function ◽  
Titanium Implants ◽  
En Bloc ◽  
Endosseous Implants ◽  
Ultrastructural Studies ◽  
The Past ◽  
Cacodylate Buffer ◽  
One Year ◽  
And Function

With increase use of tissue-integrated prostheses in recent years it is a goal to understand what is happening at the interface between haversion bone and bulk metal. This study uses electron microscopy (EM) techniques to establish parameters for osseointegration (structure and function between bone and nonload-carrying implants) in an animal model. In the past the interface has been evaluated extensively with light microscopy methods. Today researchers are using the EM for ultrastructural studies of the bone tissue and implant responses to an in vivo environment. Under general anesthesia nine adult mongrel dogs received three Brånemark (Nobelpharma) 3.75 × 7 mm titanium implants surgical placed in their left zygomatic arch. After a one year healing period the animals were injected with a routine bone marker (oxytetracycline), euthanized and perfused via aortic cannulation with 3% glutaraldehyde in 0.1M cacodylate buffer pH 7.2. Implants were retrieved en bloc, harvest radiographs made (Fig. 1), and routinely embedded in plastic. Tissue and implants were cut into 300 micron thick wafers, longitudinally to the implant with an Isomet saw and diamond wafering blade [Beuhler] until the center of the implant was reached.

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