scholarly journals Preclinical Modelling of PDA: Is Organoid the New Black?

2019 ◽  
Vol 20 (11) ◽  
pp. 2766 ◽  
Author(s):  
Sabrina D’Agosto ◽  
Silvia Andreani ◽  
Aldo Scarpa ◽  
Vincenzo Corbo
Keyword(s):  
Therapeutic Intervention ◽  
Culture System ◽  
Molecular Mechanisms ◽  
Survival Rates ◽  
Three Dimensional ◽  
Model Systems ◽  
Ductal Adenocarcinoma ◽  
Diagnostic Tools ◽  
Precision Oncology ◽  
Individual Patient Level

Pancreatic ductal adenocarcinoma (PDA) is a malignancy of the exocrine pancreas with the worst prognosis among all solid tumours, and soon to become the second leading cause of cancer-related deaths. A more comprehensive understanding of the molecular mechanisms underlying this disease is crucial to the development of diagnostic tools as well as to the identification of more effective therapies. High-frequency mutations in PDA occur in “undruggable” genes, and molecular subtyping based on bulk transcriptome analysis does not yet nominate valid therapeutic intervention strategies. Genome-wide sequencing studies have also demonstrated a considerable intra- and inter-patient’s genetic heterogeneity, which further complicate this dire scenario. More than in other malignancies, functionalization of the PDA genome and preclinical modelling at the individual patient level appear necessary to substantially improve survival rates for pancreatic cancer patients. Traditional human PDA models, including monolayer cell cultures and patient-derived xenografts, have certainly led to valuable biological insights in the past years. However, those model systems suffer from several limitations that have contributed to the lack of concordance between preclinical and clinical studies for PDA. Pancreatic ductal organoids have recently emerged as a reliable culture system to establish models from both normal and neoplastic pancreatic tissues. Pancreatic organoid cultures can be efficiently generated from small tissue biopsies, which opens up the possibility of longitudinal studies in individual patients. A proof-of-concept study has demonstrated that patient-derived PDA organoids are able to predict responses to conventional chemotherapy. The use of this three-dimensional culture system has already improved our understanding of PDA biology and promises to implement precision oncology by enabling the alignment of preclinical and clinical platforms to guide therapeutic intervention in PDA.

scholarly journals mSphere of Influence: Innate Immunity at the Maternal-Fetal Barrier

mSphere ◽  
2020 ◽  
Vol 5 (4) ◽  
Author(s):  
Kellie Ann Jurado
Keyword(s):  
Innate Immunity ◽  
Virus Infection ◽  
Culture System ◽  
Three Dimensional ◽  
Emerging Infectious Diseases ◽  
Innate Immune ◽  
Model Systems ◽  
Immune Control ◽  
Relevant Model ◽  
Link Type

ABSTRACT Kellie Ann Jurado works in the field of emerging infectious diseases. In this mSphere of Influence article, she reflects on how the papers “Type III interferons produced by human placental trophoblasts confer protection against Zika virus infection” (https://doi.org/10.1016/j.chom.2016.03.008) and “A three-dimensional culture system recapitulates placental syncytiotrophoblast development and microbial resistance” (https://doi.org/10.1126/sciadv.1501462) by Carolyn Coyne’s group have made an impact on her, inspiring her to explore immunity in the placenta by indicating the unique innate immune control elicited at the maternal-fetal barrier as well as by providing physiologically relevant model systems for study.

scholarly journals Immune Evasion in Pancreatic Cancer: From Mechanisms to Therapy

Cancers ◽  
2018 ◽  
Vol 10 (1) ◽  
pp. 6 ◽  
Author(s):  
Neus Martinez-Bosch ◽  
Judith Vinaixa ◽  
Pilar Navarro
Keyword(s):  
Pancreatic Cancer ◽  
Immune Evasion ◽  
Molecular Mechanisms ◽  
T Regulatory Cells ◽  
Immune Escape ◽  
Survival Rates ◽  
Ductal Adenocarcinoma ◽  
Cytokines And Chemokines ◽  
Tumor Recognition ◽  
Activated Fibroblasts

Pancreatic ductal adenocarcinoma (PDA), the most frequent type of pancreatic cancer, remains one of the most challenging problems for the biomedical and clinical fields, with abysmal survival rates and poor therapy efficiency. Desmoplasia, which is abundant in PDA, can be blamed for much of the mechanisms behind poor drug performance, as it is the main source of the cytokines and chemokines that orchestrate rapid and silent tumor progression to allow tumor cells to be isolated into an extensive fibrotic reaction, which results in inefficient drug delivery. However, since immunotherapy was proclaimed as the breakthrough of the year in 2013, the focus on the stroma of pancreatic cancer has interestingly moved from activated fibroblasts to the immune compartment, trying to understand the immunosuppressive factors that play a part in the strong immune evasion that characterizes PDA. The PDA microenvironment is highly immunosuppressive and is basically composed of T regulatory cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressive cells (MDSCs), which block CD8+ T-cell duties in tumor recognition and clearance. Interestingly, preclinical data have highlighted the importance of this immune evasion as the source of resistance to single checkpoint immunotherapies and cancer vaccines and point at pathways that inhibit the immune attack as a key to solve the therapy puzzle. Here, we will discuss the molecular mechanisms involved in PDA immune escape as well as the state of the art of the PDA immunotherapy.

scholarly journals Generation of focal mutations and large genomic deletions in the pancreas using inducible in vivo genome editing

2019 ◽  
Vol 41 (3) ◽  
pp. 334-344
Author(s):  
Amrendra Mishra ◽  
Fatemeh Emamgholi ◽  
Zulrahman Erlangga ◽  
Björn Hartleben ◽  
Kristian Unger ◽  
...  
Keyword(s):  
Embryonic Stem ◽  
Genetic Alterations ◽  
Model Systems ◽  
Ductal Adenocarcinoma ◽  
In Vivo Model ◽  
Precision Oncology ◽  
Kras Mutations ◽  
Genomic Deletions ◽  
The Impact

Abstract Beyond the nearly uniform presence of KRAS mutations, pancreatic cancer is increasingly recognized as a heterogeneous disease. Preclinical in vivo model systems exist, but with the advent of precision oncology, murine models with enhanced genetic flexibility are needed to functionally annotate genetic alterations found in the human malignancy. Here, we describe the generation of focal gene disruptions and large chromosomal deletions via inducible and pancreas-specific expression of Cas9 in adult mice. Experimental mice are derived on demand directly from genetically engineered embryonic stem cells, without the need for further intercrossing. To provide initial validation of our approach, we show that disruption of the E3 ubiquitin ligase Rnf43 accelerates KrasG12D-dependent tumourigenesis. Moreover, we demonstrate that this system can be used to rapidly interrogate the impact of complex cancer-associated alleles through the generation of a previously unstudied 1.2 megabase deletion surrounding the CDKN2A and CDKN2B tumour suppressors. Thus, our approach is capable of reproducibly generating biallelic and precise loss of large chromosomal fragments that, in conjunction with mutant Kras, leads to development of pancreatic ductal adenocarcinoma with full penetrance.

scholarly journals Immune Evasion in Pancreatic Cancer: from Mechanisms to Therapy

2017 ◽  
Author(s):  
Neus Martinez-Bosch ◽  
Judith Vinaixa ◽  
Pilar Navarro
Keyword(s):  
Pancreatic Cancer ◽  
Immune Evasion ◽  
Molecular Mechanisms ◽  
T Regulatory Cells ◽  
Immune Escape ◽  
Survival Rates ◽  
Ductal Adenocarcinoma ◽  
Cytokines And Chemokines ◽  
Tumor Recognition ◽  
Activated Fibroblasts

Pancreatic ductal adenocarcinoma (PDA), the most frequent type of pancreatic cancer, is one of the main unfinished businesses in the biomedical and clinical fields, with still discouraging 5 year survival rates and poor therapy efficiency. PDA abundant desmoplasia has for long played the lead in the mechanisms involved in poor drug performance, being the main source of cytokines and chemokines orchestrating rapid and silent tumor progression and guilty of isolating tumor cells into a extense fibrotic reaction resulting in inefficient drug delivery. However, since immunotherapy was proclaimed the breakthrough of the year back to 2013, the focus in the stroma of pancreatic cancer has interestingly moved from activated fibroblasts to the immune compartment, trying to understand the immunosuppressive factors that play part in the strong immune evasion that characterizes PDA. PDA microenvironment is highly immune-suppressive, being basically composed of T regulatory cells (Tregs), tumor-associated macrophages (TAMs) and myeloid-derived suppressive cells (MDSCs), which boycott CD8+ T-cell duties in tumor recognition and clearance. Interestingly, preclinical data have highlighted the importance of this immune evasion as the source of resistance to single checkpoint immunotherapies and cancer vaccines and point at pathways inhibiting the immune attack as the key to solve the therapy puzzle. Here, we will discuss the molecular mechanisms involved in PDA immune escape as well as the state of the art of the PDA immunotherapy.

scholarly journals Development in a Dish—In Vitro Models of Mammalian Embryonic Development

2021 ◽  
Vol 9 ◽  
Author(s):  
Yasmine el Azhar ◽  
Katharina F. Sonnen
Keyword(s):  
Embryonic Development ◽  
Molecular Mechanisms ◽  
Three Dimensional ◽  
In Vitro Models ◽  
Model Systems ◽  
Model Organisms ◽  
Mammalian Development ◽  
Complex Processes ◽  
Mechanisms Of Development

Despite decades of research, the complex processes of embryonic development are not fully understood. The study of mammalian development poses particular challenges such as low numbers of embryos, difficulties in culturing embryos in vitro, and the time to generate mutant lines. With new approaches we can now address questions that had to remain unanswered in the past. One big contribution to studying the molecular mechanisms of development are two- and three-dimensional in vitro model systems derived from pluripotent stem cells. These models, such as blastoids, gastruloids, and organoids, enable high-throughput screens and straightforward gene editing for functional testing without the need to generate mutant model organisms. Furthermore, their use reduces the number of animals needed for research and allows the study of human development. Here, we outline and discuss recent advances in such in vitro model systems to investigate pre-implantation and post-implantation development.

Structural Studies of Fibrinolysis by Electron and Light Microscopy

1999 ◽  
Vol 82 (08) ◽  
pp. 277-282 ◽  
Author(s):  
Yuri Veklich ◽  
Jean-Philippe Collet ◽  
Charles Francis ◽  
John W. Weisel
Keyword(s):  
Electron Microscopy ◽  
Light Microscopy ◽  
Plasminogen Activator ◽  
Structural Changes ◽  
Molecular Mechanisms ◽  
Degradation Products ◽  
Molecular Model ◽  
Three Dimensional ◽  
Tissue Type ◽  
Type Plasminogen Activator

IntroductionMuch is known about the fibrinolytic system that converts fibrin-bound plasminogen to the active protease, plasmin, using plasminogen activators, such as tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator. Plasmin then cleaves fibrin at specific sites and generates soluble fragments, many of which have been characterized, providing the basis for a molecular model of the polypeptide chain degradation.1-3 Soluble degradation products of fibrin have also been characterized by transmission electron microscopy, yielding a model for their structure.4 Moreover, high resolution, three-dimensional structures of certain fibrinogen fragments has provided a wealth of information that may be useful in understanding how various proteins bind to fibrin and the overall process of fibrinolysis (Doolittle, this volume).5,6 Both the rate of fibrinolysis and the structures of soluble derivatives are determined in part by the fibrin network structure itself. Furthermore, the activation of plasminogen by t-PA is accelerated by the conversion of fibrinogen to fibrin, and this reaction is also affected by the structure of the fibrin. For example, clots made of thin fibers have a decreased rate of conversion of plasminogen to plasmin by t-PA, and they generally are lysed more slowly than clots composed of thick fibers.7-9 Under other conditions, however, clots made of thin fibers may be lysed more rapidly.10 In addition, fibrin clots composed of abnormally thin fibers formed from certain dysfibrinogens display decreased plasminogen binding and a lower rate of fibrinolysis.11-13 Therefore, our increasing knowledge of various dysfibrinogenemias will aid our understanding of mechanisms of fibrinolysis (Matsuda, this volume).14,15 To account for these diverse observations and more fully understand the molecular basis of fibrinolysis, more knowledge of the physical changes in the fibrin matrix that precede solubilization is required. In this report, we summarize recent experiments utilizing transmission and scanning electron microscopy and confocal light microscopy to provide information about the structural changes occurring in polymerized fibrin during fibrinolysis. Many of the results of these experiments were unexpected and suggest some aspects of potential molecular mechanisms of fibrinolysis, which will also be described here.

Regulation of microRNAs in Inflammation-Associated Colorectal Cancer: A Mechanistic Approach

2020 ◽  
Vol 20 ◽  
Author(s):  
Sridhar Muthusami ◽  
Ilangovan Ramachandran ◽  
Sneha Krishnamoorthy ◽  
Yuvaraj Sambandam ◽  
Satish Ramalingam ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Colorectal Carcinogenesis ◽  
Model Systems ◽  
Necrosis Factor Alpha ◽  
Multi Stage ◽  
Mechanistic Approach ◽  
Tnf Α ◽  
Factor Alpha

: The development of colorectal cancer (CRC) is a multi-stage process. The inflammation of the colon as in inflammatory bowel disease (IBD) such as ulcerative colitis (UC) or Crohn’s disease (CD) is often regarded as the initial trigger for the development of CRC. Many cytokines such as tumor necrosis factor alpha (TNF-α) and several interleukins (ILs) are known to exert proinflammatory actions, and inflammation initiates or promotes tumorigenesis of various cancers, including CRC through differential regulation of microRNAs (miRNAs/miRs). miRNAs can be oncogenic miRNAs (oncomiRs) or anti-oncomiRs/tumor suppressor miRNAs, and they play key roles during colorectal carcinogenesis. However, the functions and molecular mechanisms of regulation of miRNAs involved in inflammation-associated CRC are still anecdotal and largely unknown. Consolidating the published results and offering perspective solutions to circumvent CRC, the current review is focused on the role of miRNAs and their regulation in the development of CRC. We have also discussed the model systems adapted by researchers to delineate the role of miRNAs in inflammation-associated CRC.

Casimir forces and vacuum energy

2017 ◽  
Author(s):  
Serge Reynaud ◽  
Astrid Lambrecht
Keyword(s):  
Casimir Force ◽  
Dimensional Space ◽  
Three Dimensional ◽  
Thermal Fluctuations ◽  
Model Systems ◽  
Vacuum Field ◽  
Force Measurements ◽  
Casimir Forces ◽  
Current State ◽  
Field Fluctuations

The Casimir force is an effect of quantum vacuum field fluctuations, with applications in many domains of physics. The ideal expression obtained by Casimir, valid for perfect plane mirrors at zero temperature, has to be modified to take into account the effects of the optical properties of mirrors, thermal fluctuations, and geometry. After a general introduction to the Casimir force and a description of the current state of the art for Casimir force measurements and their comparison with theory, this chapter presents pedagogical treatments of the main features of the theory of Casimir forces for one-dimensional model systems and for mirrors in three-dimensional space.

scholarly journals The TGFβ Family in Human Placental Development at the Fetal-Maternal Interface

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 453
Author(s):  
Susana M. Chuva de Sousa Lopes ◽  
Marta S. Alexdottir ◽  
Gudrun Valdimarsdottir
Keyword(s):  
Stem Cell ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Cell Model ◽  
Embryonic Stem ◽  
Model Systems ◽  
Special Focus ◽  
Placental Development

Emerging data suggest that a trophoblast stem cell (TSC) population exists in the early human placenta. However, in vitro stem cell culture models are still in development and it remains under debate how well they reflect primary trophoblast (TB) cells. The absence of robust protocols to generate TSCs from humans has resulted in limited knowledge of the molecular mechanisms that regulate human placental development and TB lineage specification when compared to other human embryonic stem cells (hESCs). As placentation in mouse and human differ considerably, it is only with the development of human-based disease models using TSCs that we will be able to understand the various diseases caused by abnormal placentation in humans, such as preeclampsia. In this review, we summarize the knowledge on normal human placental development, the placental disease preeclampsia, and current stem cell model systems used to mimic TB differentiation. A special focus is given to the transforming growth factor-beta (TGFβ) family as it has been shown that the TGFβ family has an important role in human placental development and disease.

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