scholarly journals Normalizing Tumor Vasculature to Reduce Hypoxia, Enhance Perfusion, and Optimize Therapy Uptake

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4444
Author(s):  
Kathy Matuszewska ◽  
Madison Pereira ◽  
Duncan Petrik ◽  
Jack Lawler ◽  
Jim Petrik
Keyword(s):  
Tumor Angiogenesis ◽  
Clinical Success ◽  
Tumor Hypoxia ◽  
Lymphatic Vessels ◽  
Therapy Resistance ◽  
Therapeutic Area ◽  
Comprehensive Understanding ◽  
Angiogenic Therapy ◽  
Tumor Growth And Metastasis ◽  
And Function

A basic requirement of tumorigenesis is the development of a vascular network to support the metabolic requirements of tumor growth and metastasis. Tumor vascular formation is regulated by a balance between promoters and inhibitors of angiogenesis. Typically, the pro-angiogenic environment created by the tumor is extremely aggressive, resulting in the rapid vessel formation with abnormal, dysfunctional morphology. The altered morphology and function of tumor blood and lymphatic vessels has numerous implications including poor perfusion, tissue hypoxia, and reduced therapy uptake. Targeting tumor angiogenesis as a therapeutic approach has been pursued in a host of different cancers. Although some preclinical success was seen, there has been a general lack of clinical success with traditional anti-angiogenic therapeutics as single agents. Typically, following anti-angiogenic therapy, there is remodeling of the tumor microenvironment and widespread tumor hypoxia, which is associated with development of therapy resistance. A more comprehensive understanding of the biology of tumor angiogenesis and insights into new clinical approaches, including combinations with immunotherapy, are needed to advance vascular targeting as a therapeutic area.

scholarly journals Extracellular Vesicle Membrane-Associated Proteins: Emerging Roles in Tumor Angiogenesis and Anti-Angiogenesis Therapy Resistance

2020 ◽  
Vol 21 (15) ◽  
pp. 5418 ◽  
Author(s):  
Song Yi Ko ◽  
Honami Naora
Keyword(s):  
Tumor Angiogenesis ◽  
Therapy Resistance ◽  
Extracellular Vesicle ◽  
Biological Functions ◽  
Vesicle Membrane ◽  
Angiogenic Therapy ◽  
Anti Cancer ◽  
Associated Proteins ◽  
Tumor Growth And Metastasis ◽  
Prime Target

The tumor vasculature is essential for tumor growth and metastasis, and is a prime target of several anti-cancer agents. Increasing evidence indicates that tumor angiogenesis is stimulated by extracellular vesicles (EVs) that are secreted or shed by cancer cells. These EVs encapsulate a variety of biomolecules with angiogenic properties, and have been largely thought to stimulate vessel formation by transferring this luminal cargo into endothelial cells. However, recent studies have revealed that EVs can also signal to recipient cells via proteins on the vesicular surface. This review discusses and integrates emerging insights into the diverse mechanisms by which proteins associate with the EV membrane, the biological functions of EV membrane-associated proteins in tumor angiogenesis, and the clinical significance of these proteins in anti-angiogenic therapy.

scholarly journals The role of tumor-derived exosomes in tumor angiogenesis and tumor progression

2019 ◽  
Vol 32 (4) ◽  
pp. 193-202 ◽  
Author(s):  
Alicja Gluszko ◽  
Shafaq M. Mirza ◽  
Katarzyna Piszczatowska ◽  
Ireneusz Kantor ◽  
Marta Struga ◽  
...  
Keyword(s):  
Lymphatic Vessels ◽  
The Body ◽  
Term Survival ◽  
Waste Products ◽  
Angiogenic Therapy ◽  
Anti Cancer ◽  
Tumor Growth And Metastasis ◽  
Communication Pathway ◽  
Cancerous Cells

Abstract Exosomes, belonging to the group of extracellular bodies, are released by healthy as well as cancerous cells and serve as a communication pathway. Tumor-derived exosomes (TEX) possess the capacity to reprogram the function of normal cells owing to their genetic and molecular cargo. Such exosomes target endothelial cells (among others) in the tumor microenvironment to promote angiogenesis. Blood supply is essential in solid tumor growth and metastasis. The potential of pro-angiogenic changes is enhanced by an increased amount of circulating tumor-derived exosomes in the body fluids of cancer patients. A vascular network is important, since the proliferation, as well as the metastatic spread of cancer cells depends on an adequate supply of oxygen and nutrients, and the removal of waste products. New blood vessels and lymphatic vessels are formed through processes called angiogenesis and lymphangiogenesis, respectively. Angiogenesis is regulated by both activator and inhibitor molecules. Thousands of patients have received anti-angiogenic therapy to date. Despite their theoretical efficacy, anti-angiogenic treatments have not proved beneficial in terms of long-term survival. Tumor-derived exosomes carrying pro-angiogenic factors might be a target for new anti-cancer therapy.

scholarly journals Phase II trial of levocetirizine with capecitabine and bevacizumab to overcome the resistance of antiangiogenic therapies in refractory metastatic colorectal cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 763-763
Author(s):  
Manik Amin ◽  
Monica Dandona Desai ◽  
Steven Sorscher ◽  
Kian-Huat Lim ◽  
Andrea Wang-Gillam ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Clinical Success ◽  
Prospective Trial ◽  
Therapy Resistance ◽  
Open Label ◽  
Significance Level ◽  
Angiogenic Therapy ◽  
Cytokine Analysis ◽  
The Impact

763 Background: Despite clinical success of VEGF blockade in mCRC, resistance to anti-angiogenic drugs invariably develops. IL-8 and other cytokines have been implicated in resistance development to anti-angiogenic therapy. Levocetirizine is a third generation antihistamine with anti-inflammatory and IL-8 suppression properties. We conducted a phase II trial combining levocetirizine with capecitabine and bevacizumab to potentially overcome anti-angiogenic therapy resistance in patients with refractory mCRC. Methods: This was a single-center open-label prospective trial in refractory mCRC patients. Treatment consisted of oral capecitabine 850mg/m2 – 7 days on and 7 days off, IV bevacizumab 5 mg/kg every 14 days and oral levocetirizine 5 mg daily in 14 day cycles. The primary end point was PFS and secondary endpoints included ORR and tolerability. An exploratory endpoint included correlation of PFS with cytokine (IL-8 & IL-6) levels. A sample size of 36 evaluable patients could identify a median PFS of 3.4 months at a 0.05 significance level. To document cytokine changes related to levocetirizine treatment, patients were randomized to Arm A where levocetirizine was started 7 days after starting chemotherapy or to Arm B where levocetirizine was started 7 days prior to chemotherapy. For PFS determination both arms were combined for analysis. Cytokine levels were measured at baseline and with each cycle of chemotherapy (up to three cycles). Results: 43 patients were enrolled in the trial to have 36 evaluable patients. Arm A enrolled 20 patients and Arm B enrolled 23 patients. Of the patients evaluable for best response, 19 had SD and 12 had PD. Median PFS of all patients on the study was 3.4 months (ranging 0.9 to 10.6 months). Conclusions: Median PFS in the trial was comparable to and possibly better than other regimens used in the refractory setting (e.g., median PFS of 1.9 months for regorafenib). Cytokine analysis is in progress and these results and correlations with patient outcomes will be presented to assess the impact of cytokine blockade on mCRC treatment. Clinical trial information: NCT01722162.

scholarly journals Discovery of a novel RORγ antagonist with skin-restricted exposure for topical treatment of mild to moderate psoriasis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Suxing Liu ◽  
Dong Liu ◽  
Ru Shen ◽  
Di Li ◽  
Qiyue Hu ◽  
...  
Keyword(s):  
Topical Treatment ◽  
Clinical Success ◽  
Systemic Exposure ◽  
Skin Inflammation ◽  
Targeted Therapeutics ◽  
High Exposure ◽  
Structure Activity ◽  
Potential Safety ◽  
Systematic Structure ◽  
And Function

AbstractClinical success of IL-17/IL-23 pathway biologics for the treatment of moderate to severe psoriasis suggests that targeting RORγt, a master regulator for the proliferation and function of Th17 cells, could be an effective alternative. However, oral RORγ antagonists (VTP43742, TAK828) with high systemic exposure showed toxicity in phase I/II clinical trials and terminated development. To alleviate the potential safety concerns, identifying compounds with skin-restricted exposure amenable for topical use is of great interest. Systematic structure activity relationship study and multi-parameter optimization led to the discovery of a novel RORγ antagonist (SHR168442) with desired properties for a topical drug. It suppressed the transcription of IL-17 gene, leading to reduction of IL-17 cytokine secretion. It showed high exposure in skin, but low in plasma. Topical application of SHR168442 in Vaseline exhibited excellent efficacy in the imiquimod-induced and IL-23-induced psoriasis-like skin inflammation mouse models and correlated with the reduction of Th17 pathway cytokines, IL-6, TNFα and IL-17A. This work demonstrated restricted skin exposure of RORγ antagonist may provide a new topical treatment option as targeted therapeutics for mild to moderate psoriasis patients and may be suitable for the treatment of any other inflammatory disorders that are accessible locally.

scholarly journals Neurons interact with the microbiome: an evolutionary-informed perspective

Neuroforum ◽  
2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Christoph Giez ◽  
Alexander Klimovich ◽  
Thomas C. G. Bosch
Keyword(s):  
Nervous System ◽  
Neural Circuits ◽  
Current Knowledge ◽  
System Development ◽  
Nervous System Development ◽  
Comprehensive Understanding ◽  
Strategic Model ◽  
Microbe Interactions ◽  
Host Microbe Interactions ◽  
And Function

Abstract Animals have evolved within the framework of microbes and are constantly exposed to diverse microbiota. Microbes colonize most, if not all, animal epithelia and influence the activity of many organs, including the nervous system. Therefore, any consideration on nervous system development and function in the absence of the recognition of microbes will be incomplete. Here, we review the current knowledge on the nervous systems of Hydra and its role in the host–microbiome communication. We show that recent advances in molecular and imaging methods are allowing a comprehensive understanding of the capacity of such a seemingly simple nervous system in the context of the metaorganism. We propose that the development, function and evolution of neural circuits must be considered in the context of host–microbe interactions and present Hydra as a strategic model system with great basic and translational relevance for neuroscience.

scholarly journals Beyond a Passive Conduit: Implications of Lymphatic Biology for Kidney Diseases

2020 ◽  
Vol 31 (6) ◽  
pp. 1178-1190 ◽  
Author(s):  
Daniyal J. Jafree ◽  
David A. Long
Keyword(s):  
Kidney Disease ◽  
Therapeutic Potential ◽  
Kidney Diseases ◽  
Transplant Rejection ◽  
Lymphatic Vessels ◽  
Renal Physiology ◽  
Clear Fluid ◽  
Adult Kidney ◽  
And Function ◽  
Development Structure

The kidney contains a network of lymphatic vessels that clear fluid, small molecules, and cells from the renal interstitium. Through modulating immune responses and via crosstalk with surrounding renal cells, lymphatic vessels have been implicated in the progression and maintenance of kidney disease. In this Review, we provide an overview of the development, structure, and function of lymphatic vessels in the healthy adult kidney. We then highlight the contributions of lymphatic vessels to multiple forms of renal pathology, emphasizing CKD, transplant rejection, and polycystic kidney disease and discuss strategies to target renal lymphatics using genetic and pharmacologic approaches. Overall, we argue the case for lymphatics playing a fundamental role in renal physiology and pathology and treatments modulating these vessels having therapeutic potential across the spectrum of kidney disease.

scholarly journals Autophagy as a mechanism for anti-angiogenic therapy resistance

2020 ◽  
Vol 66 ◽  
pp. 75-88 ◽  
Author(s):  
Ankush Chandra ◽  
Jonathan Rick ◽  
Garima Yagnik ◽  
Manish K. Aghi
Keyword(s):  
Therapy Resistance ◽  
Angiogenic Therapy

scholarly journals Biomarkers in Tumor Angiogenesis and Anti-Angiogenic Therapy

2011 ◽  
Vol 12 (10) ◽  
pp. 7077-7099 ◽  
Author(s):  
Andreas Pircher ◽  
Wolfgang Hilbe ◽  
Isabel Heidegger ◽  
Joachim Drevs ◽  
André Tichelli ◽  
...  
Keyword(s):  
Tumor Angiogenesis ◽  
Angiogenic Therapy

scholarly journals KONTRIBUSI POSITIF ORIENTALISME: KAJIAN ATAS REINHART DOZY (1820-1883 M)

2020 ◽  
Vol 20 (1) ◽  
pp. 85
Author(s):  
Ghulam Falach
Keyword(s):  
Qualitative Research ◽  
Islamic Law ◽  
Great Influence ◽  
Literary Work ◽  
Comprehensive Understanding ◽  
Islamic History ◽  
Library Research ◽  
History Of ◽  
And Function ◽  
Islamic Civilization

The main focus of Orientalist thought is nothing but to reconstruct and influence Islamic civilization. Their enthusiasm to activate orientalism is increasingly challenged by the presence of Islam as a religion that has followers of most of the world's population. One of the actions of orientalism towards the Islamic world is to start a research movement on the Qur'an and al-Hadith which are the basis of the law and guidelines of Muslims. Not far from the critics of the Qur'an and al-Hadith, they also deconstructed aspects of the development of science, Islamic law, and even the originality of Islamic history. Some famous orientalism figures, one of them is Reinhart Dozy, a famous orientelism from the Netherlands with the concept of literacy in the history of Islamic civilization in Spain. Even though he received a lot of criticism and appreciation from both orientalists and Muslim thinkers, his literary work has had a great influence on Islamic civilization. The discussion steps of this study are entirely carried out using qualitative research that is library research. To be more useful and function properly, this paper is equipped with an explanation using the method of description, interpretation and analysis of data in each discussion. This is done, none other than to focus the discussion to produce a consistent and comprehensive understanding.

scholarly journals Development and pre-clinical testing of a novel hypoxia-activated KDAC inhibitor

2021 ◽  
Author(s):  
Anna Skwarska ◽  
Ewen Calder ◽  
Deborah Sneddon ◽  
Hannah Bolland ◽  
Maria Odyniec ◽  
...  
Keyword(s):  
Single Agent ◽  
Tumor Hypoxia ◽  
Clonogenic Survival ◽  
Therapy Resistance ◽  
Growth Delay ◽  
Pharmacokinetic Analysis ◽  
Lysine Deacetylase ◽  
Oxygen Conditions ◽  
Patient Prognosis ◽  
Induced Apoptosis

Tumor hypoxia is associated with therapy resistance and poor patient prognosis. Hypoxia-activated prodrugs, designed to selectively target hypoxic cells while sparing normal tissue, represent a promising treatment strategy. We report the pre-clinical efficacy of 1-methyl-2-nitroimidazole panobinostat (NI-Pano, CH-03), a novel bioreductive version of the clinically used lysine deacetylase inhibitor, panobinostat. NI-Pano was stable in normoxic (21% oxygen) conditions and underwent NADPH-CYP-mediated enzymatic bioreduction to release panobinostat in hypoxia (<0.1% oxygen). Treatment of cells grown in both 2D and 3D with NI-Pano increased acetylation of histone H3 at lysine 9, induced apoptosis and decreased clonogenic survival. Importantly, NI-Pano exhibited growth delay effects as a single agent in tumor xenografts. Pharmacokinetic analysis confirmed the presence of sub- micromolar concentrations of panobinostat in hypoxic mouse xenografts, but not in circulating plasma or kidneys. Together, our preclinical results provide a strong mechanistic rationale for the clinical development of NI-Pano for selective targeting of hypoxic tumors.<br>

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