Detection of risk of cancer to man

1979 ◽  
Vol 205 (1158) ◽  
pp. 111-120 ◽  
Keyword(s):  
Large Scale ◽  
Human Cancer ◽  
Environmental Pollutants ◽  
Model Systems ◽  
Fourth Power ◽  
Percentage Increase ◽  
Direct Estimate ◽  
Human Carcinogenesis ◽  
Risk Of Cancer

Epidemiology can pick out large-scale determinants of human cancer, such as smoking. Also, epidemiology can pick out carcinogens such as asbestos to which groups of perhaps a few hundred or a few thousand workers have been heavily exposed for decades. However, if highly exposed groups cannot be studied then epidemiology cannot recognize carcinogens which, although perhaps widely distributed, produce only a small percentage increase in particular cancers. Almost all of the environmental pollutants that can affect human cancer incidence will do so only to a very minor extent, at the levels to which we are currently exposed. For this reason, and also because it is often difficult to define an exposed and an unexposed group which do not differ in other ways as well, it will almost always be impossible to do anything epidemiologically except to set a very crude upper limit on their likely hazards. The only way, therefore, to get any direct estimate of these hazards is by laboratory studies of the effects of high doses on various model systems. For this and for other reasons, it would be highly desirable to have good laboratory models for human carcinogenesis. The characteristics required of satisfactory laboratory systems are reviewed, and it is argued that systematic errors may arise unless one studies epithelial cells from large, long-lived species under conditions of chronic, low-dose exposure to noxious test agents in conjunction with standard chronic doses of agents which may be synergistic with the test agents. (Carcinogenic mutagens may be synergistic with carcinogenic non-mutagens.) For reasons of expense and speed, such studies must be done in vitro . If such in-vitro systems can be developed, either by using tissue explants or cell cultures, an important criterion which they will have to satisfy to be trusted will be that under chronic exposure the rate of transformation should be proportional to something like the fourth power of exposure duration. This paper chiefly reviews the reasons for choosing these specifications for a trustworthy in-vitro model for human carcinogenesis.

scholarly journals Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma

2016 ◽  
Vol 113 (42) ◽  
pp. E6409-E6417 ◽  
Author(s):  
David G. McFadden ◽  
Katerina Politi ◽  
Arjun Bhutkar ◽  
Frances K. Chen ◽  
Xiaoling Song ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Mouse Models ◽  
Cancer Progression ◽  
Large Scale ◽  
Human Cancer ◽  
Genetically Engineered ◽  
Model Systems ◽  
Driver Mutations ◽  
Genetic Profile ◽  
Genetically Engineered Mouse Models

Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity.

scholarly journals Unbiased in vivo preclinical evaluation of anticancer drugs identifies effective therapy for the treatment of pancreatic adenocarcinoma

2020 ◽  
Vol 117 (48) ◽  
pp. 30670-30678
Author(s):  
Olivera Grbovic-Huezo ◽  
Kenneth L. Pitter ◽  
Nicolas Lecomte ◽  
Joseph Saglimbeni ◽  
Gokce Askan ◽  
...  
Keyword(s):  
Large Scale ◽  
Single Agent ◽  
Model Systems ◽  
Ductal Adenocarcinoma ◽  
In Vivo Model ◽  
Cancer Therapies ◽  
Hsp90 Inhibition ◽  
Dismal Prognosis

Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at an advanced stage, which limits surgical options and portends a dismal prognosis. Current oncologic PDAC therapies confer marginal benefit and, thus, a significant unmet clinical need exists for new therapeutic strategies. To identify effective PDAC therapies, we leveraged a syngeneic orthotopic PDAC transplant mouse model to perform a large-scale, in vivo screen of 16 single-agent and 41 two-drug targeted therapy combinations in mice. Among 57 drug conditions screened, combined inhibition of heat shock protein (Hsp)-90 and MEK was found to produce robust suppression of tumor growth, leading to an 80% increase in the survival of PDAC-bearing mice with no significant toxicity. Mechanistically, we observed that single-agent MEK inhibition led to compensatory activation of resistance pathways, including components of the PI3K/AKT/mTOR signaling axis, which was overcome with the addition of HSP90 inhibition. The combination of HSP90(i) + MEK(i) was also active in vitro in established human PDAC cell lines and in vivo in patient-derived organoid PDAC transplant models. These findings encourage the clinical development of HSP90(i) + MEK(i) combination therapy and highlight the power of clinically relevant in vivo model systems for identifying cancer therapies.

scholarly journals Bimodality of gene expression in cancer patient tumors as interpretable biomarkers for drug sensitivity

2020 ◽  
Author(s):  
Wail Ba-Alawi ◽  
Sisira Kadambat Nair ◽  
Bo Li ◽  
Anthony Mammoliti ◽  
Petr Smirnov ◽  
...  
Keyword(s):  
Machine Learning ◽  
Large Scale ◽  
Human Cancer ◽  
Predictive Biomarkers ◽  
Precision Oncology ◽  
Human Cancer Cell Lines ◽  
Validation Rate ◽  
Approved Drugs ◽  
Pharmacogenomic Studies

ABSTRACTIdentifying biomarkers predictive of cancer cells’ response to drug treatment constitutes one of the main challenges in precision oncology. Recent large-scale cancer pharmacogenomic studies have boosted the research for finding predictive biomarkers by profiling thousands of human cancer cell lines at the molecular level and screening them with hundreds of approved drugs and experimental chemical compounds. Many studies have leveraged these data to build predictive models of response using various statistical and machine learning methods. However, a common challenge in these methods is the lack of interpretability as to how they make the predictions and which features were the most associated with response, hindering the clinical translation of these models. To alleviate this issue, we develop a new machine learning pipeline based on the recent LOBICO approach that explores the space of bimodally expressed genes in multiple large in vitro pharmacogenomic studies and builds multivariate, nonlinear, yet interpretable logic-based models predictive of drug response. Using our method, we used a compendium of three of the largest pharmacogenomic data sets to build robust and interpretable models for 101 drugs that span 17 drug classes with high validation rate in independent datasets.

scholarly journals Egyptian Arthrospira phytosterols: production, identification, antioxidant and antiproliferative activities

2020 ◽  
Vol 48 (2) ◽  
pp. 666-680
Author(s):  
Gamal S. El BAROTY ◽  
Hanaa H. Abd El BAKY ◽  
Mahmoud A. SALEH
Keyword(s):  
Total Lipid ◽  
Large Scale ◽  
Human Cancer ◽  
Radical Scavenging Activity ◽  
Colorimetric Method ◽  
Radical Scavenging ◽  
Human Cancer Cell Lines ◽  
Ic50 Values ◽  
Antiproliferative Activities

Cultivation of microalgae as a source of phytosterol and other lipid compounds has gained more attention for commercial applications in pharmaceutical, cosmetic and food function industries. In this research, native Spirulina maxima SM from Egypt was grown in individual cultures containing various concentrations of nitrogen (N), phosphorus (P) and sulfur (S) elements in order to elucidate the effect of its elements on lipid and phytosterols production and to evaluate its antioxidant and antiproliferative activities. The results revealed that the SM was able to grow in different concentrations of testing elements S (from 0.3 to 2.4 mM), P (from 0.3 to 2.4 mM) and N (0.3 to 3.2 mM) with significant differences. A high potential for production of MS biomass, total lipid and phytosterol contents were obtained in individual cultures containing 0.6 mM N, 0.6 mM P and 0.80 mM, respectively. Therefore, these concentrations (combination of S+P+N element) were selected for cultivation of SM at large scale in a column photobioreactor (PBR 300 L) to induce sufficient SM biomass so that, we can obtain an adequate amount of total lipid and phytosterol contents. Phytosterols (PS) of native SM grown in the 300 L PBR were partially purified from unsaponified extracts of SM total lipid followed by its purification by crystallization process. The identification and quantification of PS profile were performed by GC-FID analysis. The results revealed high levels of campsterol, D7-Avena sterol, β-sitosterol, stigmasterol and other compounds. These PS compounds showed marked in vitro superoxide, DPPH and .OH radical scavenging activity, which was comparable with the results obtained with standard antioxidants BHA or α-tocopherol. Moreover, SM phytosterols exhibited anti-proliferative activity against three human cancer cell lines (MCF-7, Hep-G2 and HCT-116) with IC50 values less than 11.62 µg/mL as assessed by in vitro MTT colorimetric method. Thus, SM phytosterol may be considered as a potential natural source of promising ingredient in the future for a range of health applications for human, cosmetic industries and in functional food.

scholarly journals Recent progress in translational engineered in vitro models of the central nervous system

Brain ◽  
2020 ◽  
Vol 143 (11) ◽  
pp. 3181-3213 ◽  
Author(s):  
Polyxeni Nikolakopoulou ◽  
Rossana Rauti ◽  
Dimitrios Voulgaris ◽  
Iftach Shlomy ◽  
Ben M Maoz ◽  
...  
Keyword(s):  
Large Scale ◽  
Induced Pluripotent Stem Cell ◽  
In Vitro Models ◽  
Model Systems ◽  
Success Rates ◽  
Recent Developments ◽  
Practical Guidelines ◽  
Organ On A Chip ◽  
Induced Pluripotent

Abstract The complexity of the human brain poses a substantial challenge for the development of models of the CNS. Current animal models lack many essential human characteristics (in addition to raising operational challenges and ethical concerns), and conventional in vitro models, in turn, are limited in their capacity to provide information regarding many functional and systemic responses. Indeed, these challenges may underlie the notoriously low success rates of CNS drug development efforts. During the past 5 years, there has been a leap in the complexity and functionality of in vitro systems of the CNS, which have the potential to overcome many of the limitations of traditional model systems. The availability of human-derived induced pluripotent stem cell technology has further increased the translational potential of these systems. Yet, the adoption of state-of-the-art in vitro platforms within the CNS research community is limited. This may be attributable to the high costs or the immaturity of the systems. Nevertheless, the costs of fabrication have decreased, and there are tremendous ongoing efforts to improve the quality of cell differentiation. Herein, we aim to raise awareness of the capabilities and accessibility of advanced in vitro CNS technologies. We provide an overview of some of the main recent developments (since 2015) in in vitro CNS models. In particular, we focus on engineered in vitro models based on cell culture systems combined with microfluidic platforms (e.g. ‘organ-on-a-chip’ systems). We delve into the fundamental principles underlying these systems and review several applications of these platforms for the study of the CNS in health and disease. Our discussion further addresses the challenges that hinder the implementation of advanced in vitro platforms in personalized medicine or in large-scale industrial settings, and outlines the existing differentiation protocols and industrial cell sources. We conclude by providing practical guidelines for laboratories that are considering adopting organ-on-a-chip technologies.

scholarly journals An overview of the potential anticancer properties of cardamonin

2020 ◽  
Vol 1 (6) ◽  
Author(s):  
Shanaya Ramchandani ◽  
Irum Naz ◽  
Namrata Dhudha ◽  
Manoj Garg
Keyword(s):  
Anticancer Agent ◽  
Human Cancer ◽  
Model Systems ◽  
Preclinical Model ◽  
Cancer Treatments ◽  
Human Cancer Cell Lines ◽  
Anticancer Properties ◽  
Natural Medicine

Cancer is one of the leading causes of mortality, contributing to 9.6 million deaths globally in 2018 alone. Although several cancer treatments exist, they are often associated with severe side effects and high toxicities, leaving room for significant advancements to be made in the field. In recent years, several phytochemicals from plants and natural bioresources have been extracted and tested against various human malignancies using both in vitro and in vivo preclinical model systems. Cardamonin, a chalcone extracted from the Alpinia species, is an example of a natural therapeutic agent that has anti-cancer and anti-inflammatory effects against human cancer cell lines, including breast, lung, colon, and gastric, in both in vitro culture systems as well as xenograft mouse models. Earlier, cardamonin was used as a natural medicine against stomach related issues, diarrhea, insulin resistance, nephroprotection against cisplatin treatment, vasorelaxant and antinociceptive. The compound is well-known to inhibit proliferation, migration, invasion, and induce apoptosis, through the involvement of Wnt/β-catenin, NF-κB, and PI3K/Akt pathways. The good biosafety and pharmacokinetic profiling of cardamonin satisfy it as an attractive molecule for the development of an anticancer agent. The present review has summarized the chemo-preventive ability of cardamonin as an anticancer agent against numerous human malignancies.

scholarly journals Modeling the function of BAX and BAK in early human brain development using iPSC-derived systems

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Piyush Joshi ◽  
Caroline Bodnya ◽  
Megan L. Rasmussen ◽  
Alejandra I. Romero-Morales ◽  
Anna Bright ◽  
...  
Keyword(s):  
Human Brain ◽  
Brain Development ◽  
Neural Development ◽  
Human Cancer ◽  
Model Systems ◽  
Mitochondrial Morphology ◽  
Double Knockout ◽  
Human Brain Development ◽  
Early Human

Abstract Intrinsic apoptosis relies on the ability of the BCL-2 family to induce the formation of pores on the outer mitochondrial membrane. Previous studies have shown that both BAX and BAK are essential during murine embryogenesis, and reports in human cancer cell lines identified non-canonical roles for BAX and BAK in mitochondrial fission during apoptosis. BAX and BAK function in human brain development remains elusive due to the lack of appropriate model systems. Here, we generated BAX/BAK double knockout human-induced pluripotent stem cells (hiPSCs), hiPSC-derived neural progenitor cells (hNPCs), neural rosettes, and cerebral organoids to uncover the effects of BAX and BAK deletion in an in vitro model of early human brain development. We found that BAX and BAK-deficient cells have abnormal mitochondrial morphology and give rise to aberrant cortical structures. We suggest crucial functions for BAX and BAK during human development, including maintenance of homeostatic mitochondrial morphology, which is crucial for proper development of progenitors and neurons of the cortex. Human pluripotent stem cell-derived systems can be useful platforms to reveal novel functions of the apoptotic machinery in neural development.

Large-scale in vitro expansion of polyclonal human CD4+CD25high regulatory T cells

Blood ◽  
2004 ◽  
Vol 104 (3) ◽  
pp. 895-903 ◽  
Author(s):  
Petra Hoffmann ◽  
Ruediger Eder ◽  
Leoni A. Kunz-Schughart ◽  
Reinhard Andreesen ◽  
Matthias Edinger
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Application ◽  
Large Scale ◽  
Treg Cells ◽  
Model Systems ◽  
High Dose ◽  
Solid Organ ◽  
Potential Clinical Application

AbstractCD4+CD25+ regulatory T (Treg) cells are pivotal for the maintenance of self-tolerance, and their adoptive transfer gives protection from autoimmune diseases and pathogenic alloresponses after solid organ or bone marrow transplantation in murine model systems. In vitro, human CD4+CD25+ Treg cells display phenotypic and functional characteristics similar to those of murine CD4+CD25+ Treg cells: namely, hyporesponsiveness to T-cell receptor (TCR) stimulation and suppression of CD25- T cells. Thus far, the detailed characterization and potential clinical application of human CD4+CD25+ Treg cells have been hampered by their paucity in peripheral blood and the lack of appropriate expansion protocols. Here we describe the up to 40 000-fold expansion of highly purified human CD4+CD25high T cells in vitro through the use of artificial antigen-presenting cells for repeated stimulation via CD3 and CD28 in the presence of high-dose interleukin 2 (IL-2). Expanded CD4+CD25high T cells were polyclonal, maintained their phenotype, exceeded the suppressive activity of freshly isolated CD4+CD25high T cells, and maintained expression of the lymph node homing receptors L-selectin (CD62L) and CCR7. The ability to rapidly expand human CD4+CD25high Treg cells on a large scale will not only facilitate their further exploration but also accelerate their potential clinical application in T cell–mediated diseases and transplantation medicine.

scholarly journals SI113, a Specific Inhibitor of the Sgk1 Kinase Activity that Counteracts Cancer Cell Proliferation

2015 ◽  
Vol 35 (5) ◽  
pp. 2006-2018 ◽  
Author(s):  
Lucia D''Antona ◽  
Rosario Amato ◽  
Cristina Talarico ◽  
Francesco Ortuso ◽  
Miranda Menniti ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Kinase Inhibitor ◽  
Human Cancer ◽  
P53 Protein ◽  
Single Agent ◽  
Specific Inhibitor ◽  
Human Colon ◽  
Model Systems ◽  
Human Colon Carcinoma Cell

Background/Aims: Published observations on serum and glucocorticoid regulated kinase 1 (Sgk1) knockout murine models and Sgk1-specific RNA silencing in the RKO human colon carcinoma cell line point to this kinase as a central player in colon carcinogenesis and in resistance to taxanes. Methods: By in vitro kinase activity inhibition assays, cell cycle and viability analysis in human cancer model systems, we describe the biologic effects of a recently identified kinase inhibitor, SI113, characterized by a substituted pyrazolo[3,4-d]pyrimidine scaffold, that shows specificity for Sgk1. Results: SI113 was able to inhibit in vitro cell growth in cancer cells derived from tumors with different origins. In RKO cells, this kinase inhibitor blocked insulin-dependent phosphorylation of the Sgk1 substrate Mdm2, the main regulator of p53 protein stability, and induced necrosis and apoptosis when used as a single agent. Finally, SI113 potentiated the effects of paclitaxel on cell viability. Conclusion: Since SI113 appears to be effective in inducing cell death in RKO cells, potentiating paclitaxel sensitivity, we believe that this new molecule could be efficiently employed, alone or in combination with paclitaxel, in colon cancer chemotherapy.

scholarly journals Functional 3-Dimensional Retinal Organoids: Technological Progress and Existing Challenges

2021 ◽  
Vol 15 ◽  
Author(s):  
Meimanat Fathi ◽  
Cody T. Ross ◽  
Zohreh Hosseinzadeh
Keyword(s):  
Large Scale ◽  
Model Systems ◽  
Artificial Organs ◽  
Human Model ◽  
Biomedical Sciences ◽  
3 Dimensional ◽  
Retinal Tissue ◽  
Cell Transplants ◽  
Functional Features

Stem cell scientists have developed methods for the self-formation of artificial organs, often referred to as organoids. Organoids can be used as model systems for research in multiple biological disciplines. Yoshiki Sasai’s innovation for deriving mammalian retinal tissue from in vitro stem cells has had a large impact on the study of the biology of vision. New developments in retinal organoid technology provide avenues for in vitro models of human retinal diseases, studies of pathological mechanisms, and development of therapies for retinal degeneration, including electronic retinal implants and gene therapy. Moreover, these innovations have played key roles in establishing models for large-scale drug screening, studying the stages of retinal development, and providing a human model for personalized therapeutic approaches, like cell transplants to replace degenerated retinal cells. Here, we first discuss the importance of human retinal organoids to the biomedical sciences. Then, we review various functional features of retinal organoids that have been developed. Finally, we highlight the current limitations of retinal organoid technologies.

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