On the Impact of Chemo-Mechanically Induced Phenotypic Transitions in Gliomas

Tumor microenvironment is a critical player in glioma progression, and novel therapies for its targeting have been recently proposed. In particular, stress-alleviation strategies act on the tumor by reducing its stiffness, decreasing solid stresses and improving blood perfusion. However, these microenvironmental changes trigger chemo–mechanically induced cellular phenotypic transitions whose impact on therapy outcomes is not completely understood. In this work we analyze the effects of mechanical compression on migration and proliferation of glioma cells. We derive a mathematical model of glioma progression focusing on cellular phenotypic plasticity. Our results reveal a trade-off between tumor infiltration and cellular content as a consequence of stress-alleviation approaches. We discuss how these novel findings increase the current understanding of glioma/microenvironment interactions and can contribute to new strategies for improved therapeutic outcomes.

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On the impact of chemo-mechanically induced phenotypic transitions in gliomas

10.1101/476150 ◽

2018 ◽

Author(s):

Pietro Mascheroni ◽

Juan Carlos Lopez Alfonso ◽

Maria Kalli ◽

Triantafyllos Stylianopoulos ◽

Michael Meyer-Hermann ◽

...

Keyword(s):

Glioma Cell ◽

Blood Perfusion ◽

Tumor Infiltration ◽

Mechanical Compression ◽

Therapy Outcomes ◽

Stress Alleviation ◽

Therapeutic Outcomes ◽

The Impact ◽

Glioma Microenvironment ◽

Glioma Progression

ABSTRACTTumor microenvironment is a critical player in glioma progression and novel therapies for its targeting have been recently proposed. In particular, stress-alleviation strategies act on the tumor by reducing its stiffness, decreasing solid stresses and improving blood perfusion. However, these microenvironmental changes trigger chemo-mechanically induced cellular phenotypic transitions whose impact on therapy outcomes is not completely understood. In this work, we perform experiments to analyze the effects of mechanical compression on migration and proliferation of two glioma cell lines. From these experiments, we derive a mathematical model of glioma progression focusing on cellular phenotypic plasticity. The model reveals a trade-off between tumor infiltration and cellular content as a consequence of stress-alleviation approaches. We discuss how these findings can improve the current understanding of glioma/microenvironment interactions, and suggest strategies to improve therapeutic outcomes.

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SorCS3 Promotes the Internalization of p75NTR to Inhibit Glioma Progression

10.21203/rs.3.rs-548754/v1 ◽

2021 ◽

Author(s):

Yanqiu Zhang ◽

Yue Li ◽

Yuhua Fan ◽

Baoshan Zhao ◽

Huan Liang ◽

...

Keyword(s):

Glioma Cells ◽

Tissue Microarrays ◽

Cell Receptor ◽

Receptor Internalization ◽

Cellular Signal ◽

Proliferation And Metastasis ◽

The Impact ◽

Glioma Progression

Abstract Background: Glioma is a fatal malignancy caused by dysregulation of cellular signal transduction. Internalization plays a key role in maintaining signalling balance. SorCS3 is involved in nerve cell receptor internalization. However, the impact of SorCS3 on the biological processes involved in glioma has not yet been reported. Here, we highlight the potential of SorCS3-mediated regulation of signalling receptor internalization as a rational target for therapeutic intervention in glioma.Methods: SorCS3 expression was analysed in the TCGA and CGGA databases and in tissue microarrays. The effects of SorCS3 on the proliferation and metastasis of glioma cells were examined in vitro and in vivo with Transwell, wound healing, EdU incorporation and nude mouse tumorigenicity assays. Fluorescent 5-FAM, SE-labelled proteins were used to detect the internalization of SorCS3 in glioma cells. Immunofluorescence and Co-IP assays were conducted to investigate the downstream effector of SorCS3. Moreover, Dynasore and Ro 08-2750, inhibitors of internalization and NGF binding to p75NTR, respectively, were used to validate the biological functions of SorCS3 in glioma.Results: Our data demonstrated that SorCS3 was downregulated in glioma tissues and closely related to favourable prognosis. Overexpression of SorCS3 inhibited the proliferation and metastasis of glioma cells in vitro and in vivo, while silencing of SorCS3 exerted the opposite effects. Mechanistic investigations showed that SorCS3 bound to p75NTR, which subsequently increased the internalization of p75NTR, and then transported p75NTR to the lysosome for degradation, ultimately contributing to inhibition of glioma progression.Conclusions: Our work suggests that SorSC3 is a marker of promising prognosis in glioma patients and suggests that SorCS3 regulates internalization, which plays an important role in inhibiting glioma progression.

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The mathematics of multiple lockdowns

Scientific Reports ◽

10.1038/s41598-021-87556-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Antonio Scala

Keyword(s):

Beneficial Effect ◽

Epidemic Model ◽

Final Size ◽

Optimal Response ◽

Support Strategy ◽

The Impact ◽

New Strategies

AbstractWhile vaccination is the optimal response to an epidemic, recent events have obliged us to explore new strategies for containing worldwide epidemics, like lockdown strategies, where the contacts among the population are strongly reduced in order to slow down the propagation of the infection. By analyzing a classical epidemic model, we explore the impact of lockdown strategies on the evolution of an epidemic. We show that repeated lockdowns have a beneficial effect, reducing the final size of the infection, and that they represent a possible support strategy to vaccination policies.

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Inhibitory Effect of MicroRNA-376b-Overexpressing Bone Marrow Mesenchymal Stem Cells (BMSCs) on Malignant Characteristics of Glioma Cells Through Targeting Forkhead Box Protein P2 (FOXP2)

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2022.2999 ◽

2022 ◽

Vol 12 (5) ◽

pp. 971-977

Author(s):

Ruoyu Zhu ◽

Zhonglin Wang

Keyword(s):

Glioma Cell ◽

Potential Role ◽

Glioma Cells ◽

Inhibitory Effect ◽

Transwell Assay ◽

Cell Behaviors ◽

Forkhead Box ◽

Marrow Mesenchymal Stem Cells ◽

The Impact

This study investigated the impact of microRNA (miR)-376b derived from BMSCs on glioma progression. BMSCs were transfected with miR-376b mimic, miR-376b inhibitor or NC and then cocultured with glioma cells followed by measuring cell behaviors by MTT assay, Transwell assay and flow cytometry, FOXP2 and miR-376b expression by Western blot and RT-qPCR. After confirming the inhibitory and mimicking activity of transfection, we found that overexpression of miR-376b in BMSCs decreased glioma cell invasion, migration and proliferation but promoted cell apoptosis within 24 h and 48 h after transfection along with reduced number of cells in S-phase. Mechanically, miR-376b targeted miR-376b and up-regulation of miR-376b caused down-regulation of FOXP2 (p < 0.05). Overexpression of miR-376b in BMSCs decelerated glioma cell cycle and inhibitedmalignant behaviors of glioma cells by targeting FOXP2 expression. These evidence unveils the potential role of FOXP2 as a biomarker for the treatment of gliomas.

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Postgraduate medical education during the COVID-19 pandemic: lessons learned and calls to action for medical education leaders

Canadian Journal of Physician Leadership ◽

10.37964/cr24740 ◽

2021 ◽

Vol 7 (4) ◽

pp. 145-152

Author(s):

Leanna S McKenzie ◽

Amonpreet K Sandhu

Keyword(s):

Medical Education ◽

Virtual World ◽

Postgraduate Medical Education ◽

Educational Leaders ◽

Lessons Learned ◽

Education Leaders ◽

Education Delivery ◽

The Impact ◽

Rapid Transformation ◽

New Strategies

The COVID-19 pandemic has led to a rapid transformation in the delivery of postgraduate medical education, causing unexpected effects on the learning experiences of residents in training. Program directors, as educational leaders, are relied on to adapt an established curriculum and clinical experience into a virtual world while navigating the limitations imposed by the pandemic. In this article, we focus on the impact of the dramatic changes to medical education delivery on both learners and leaders and examine the challenges and successes of the new strategies employed. A reflection of the importance of leadership in medical education is discussed, along with a review of the strategies that have emerged as successful and worthy of integration into our new medical education paradigm.

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BRMS1 Suppresses Glioma Progression by Regulating Invasion, Migration and Adhesion of Glioma Cells

PLoS ONE ◽

10.1371/journal.pone.0098544 ◽

2014 ◽

Vol 9 (5) ◽

pp. e98544 ◽

Cited By ~ 12

Author(s):

Pengjin Mei ◽

Jin Bai ◽

Meilin Shi ◽

Qinghua Liu ◽

Zhonglin Li ◽

...

Keyword(s):

Glioma Cells ◽

Glioma Progression

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Can the Application of the Human Rights of the Child in a Criminal Case Result in a Therapeutic Outcome

Potchefstroom Electronic Law Journal/Potchefstroomse Elektroniese Regsblad ◽

10.17159/1727-3781/2010/v13i3a2680 ◽

2017 ◽

Vol 13 (3) ◽

pp. 125

Author(s):

Enid Coetzee

Keyword(s):

Human Rights ◽

Case Law ◽

Primary Caregiver ◽

Therapeutic Outcome ◽

Specific Reference ◽

Rights Of The Child ◽

Therapeutic Outcomes ◽

The Republic ◽

Mitigating Factor ◽

The Impact

Prior to the change brought about by S v M,[1] the interests of children were only considered as a circumstance or mitigating factor of the offender during the sentencing process. The article will discuss case law in order to determine the impact that the inclusion of the human rights of the child had on the sentencing process if the offender was the primary caregiver of the child. Specific reference is made to Sections 28(2) and 28(1)(b) of the Constitution of the Republic of South Africa, 1996. The article will then consider whether this inclusion might improve therapeutic outcomes without the apprehension that the interests of justice would be forfeited. A therapeutic outcome is brought about when the attention is placed on the human, emotional and psychological side of the law. It is concluded that the Zinn triad remains the basic measure to be used by sentencing courts to determine an appropriate sentence. Should the sentence be direct imprisonment, the court has to ensure that the children receive appropriate care as prescribed by Section 28(1)(b). Should a range of sentences be considered, even though the court has a wide discretion to decide which factors should be allowed to influence the measure of punishment, when the offender is a primary caregiver, Section 28(2) must be included as an independent factor. It is also concluded from the case law discussion that the inclusion of the human rights of the child in the sentencing process did not automatically give rise to a therapeutic outcome, although in some judgments it did result in a therapeutic outcome. Thus, the consideration of the human rights of the children during the sentencing process creates the opportunity for a therapeutic outcome.[1] 2007 2 SACR 539 (CC).

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TMIC-58. THE CELLULAR AND MOLECULAR BASIS FOR MESENCHYMAL TRANSFORMATION IN GLIOMAS

Neuro-Oncology ◽

10.1093/neuonc/noz175.1092 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi260-vi260

Author(s):

Andrea Comba ◽

Patrick J Dunn ◽

Anna E Argento ◽

Padma Kadiyala ◽

Sebastien Motsch ◽

...

Keyword(s):

Tumor Progression ◽

Tumor Cells ◽

Smooth Muscle Actin ◽

Glioma Cells ◽

Time Lapse ◽

Mesenchymal Cells ◽

Genetically Engineered ◽

Normal Brain ◽

Mesenchymal Transformation ◽

Glioma Progression

Abstract Mesenchymal gliomas are the most aggressive tumors that carry the worst prognosis. The origins of mesenchymal cells within brain tumors, remains poorly understood. They could originate either from invading mesenchymal cells, from perivascular smooth muscle actin+ cells, or from a mesenchymal transformation of tumor cells. Identifying the origin and function of mesenchymal cells within gliomas is essential as these cells contribute to increased glioma aggressiveness and tumor progression. In this study we used human biopsies and implantable and genetically engineered mouse models (GEMM) of GBM to study tumor mesenchymal transformation. GBM implantable models were used to analyze the molecular landscape by laser microdissection followed by RNA-Seq and bioinformatics analysis. Time lapse confocal imagining was implemented to analyze GBM cells dynamics. Our results indicate the existence of a complex intratumoral and peritumoral dynamic organization of glioma cells (i.e., Oncostreams). Multicellular structures of elongated cells compatible with mesenchymal differentiation. These structures play important roles in intratumoral movements, peritumoral invasion of normal brain, and overall glioma progression. We also show that oncostreams are molecularly distinct and display increased expression of mesenchymal genes such as Col1a1. Knocking down of Col1a1 in a GEMM of aggressive gliomas reduced tumor progression and significantly increased animal survival. Histological examination confirmed absence of Col1a1, and absence of morphologically identifiable oncostreams. Our results show that tumor cells, especially within oncostreams, display a fibroblastic-like morphology and express proteins typical of mesenchymal cells. The knockout of Col1a1 from tumoral cells eliminated oncostreams from tumors and delayed tumor progression. These data suggest that tumor cells expressing mesenchymal genes regulate the organization of mesenchymal multicellular structures, and determine glioma progression. We propose that inhibiting mesenchymal transformation of glioma cells will assist in the treatment of glioblastoma.

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Nano-Biomimetic Drug Delivery Vehicles: Potential Approaches for COVID-19 Treatment

Molecules ◽

10.3390/molecules25245952 ◽

2020 ◽

Vol 25 (24) ◽

pp. 5952

Author(s):

Bwalya A. Witika ◽

Pedzisai A. Makoni ◽

Larry L. Mweetwa ◽

Pascal V. Ntemi ◽

Melissa T. R. Chikukwa ◽

...

Keyword(s):

Drug Delivery ◽

Targeted Delivery ◽

Inflammatory Diseases ◽

Cell Types ◽

Charge Composition ◽

Drug Delivery Vehicles ◽

Therapeutic Outcomes ◽

Delivery Vehicles ◽

The Impact

The current COVID-19 pandemic has tested the resolve of the global community with more than 35 million infections worldwide and numbers increasing with no cure or vaccine available to date. Nanomedicines have an advantage of providing enhanced permeability and retention and have been extensively studied as targeted drug delivery strategies for the treatment of different disease. The role of monocytes, erythrocytes, thrombocytes, and macrophages in diseases, including infectious and inflammatory diseases, cancer, and atherosclerosis, are better understood and have resulted in improved strategies for targeting and in some instances mimicking these cell types to improve therapeutic outcomes. Consequently, these primary cell types can be exploited for the purposes of serving as a “Trojan horse” for targeted delivery to identified organs and sites of inflammation. State of the art and potential utilization of nanocarriers such as nanospheres/nanocapsules, nanocrystals, liposomes, solid lipid nanoparticles/nano-structured lipid carriers, dendrimers, and nanosponges for biomimicry and/or targeted delivery of bioactives to cells are reported herein and their potential use in the treatment of COVID-19 infections discussed. Physicochemical properties, viz., hydrophilicity, particle shape, surface charge, composition, concentration, the use of different target-specific ligands on the surface of carriers, and the impact on carrier efficacy and specificity are also discussed.

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