IN VITRO TESTING OF POTENT ANTI-CMV AGENTS: DEVELOPMENT OF NOVEL THERAPEUTIC INTERVENTION

SummaryUrokinase and urokinase-activated plasmin have been given to the dog and rabbit. A thrombolytic state has been induced. Purified urokinase has induced lysis of the experimental radioactive blood clot embolus in the circulation. Demonstration of effectiveness in this animal experiment is hampered by inhibition of the agents in the circulation to a degree much greater than was noted in previous experiments with streptokinase. In vitro testing indicates that under proper conditions urokinase will be an effective agent in the treatment of human thromboembolism.

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Platelet-derived lysophosphatidic acid mediated LPAR1 activation as a therapeutic target for osteosarcoma metastasis

Oncogene ◽

10.1038/s41388-021-01956-6 ◽

2021 ◽

Author(s):

Satoshi Takagi ◽

Yuki Sasaki ◽

Sumie Koike ◽

Ai Takemoto ◽

Yosuke Seto ◽

...

Keyword(s):

Platelet Activation ◽

Pulmonary Metastasis ◽

Lysophosphatidic Acid ◽

Therapeutic Intervention ◽

Molecular Mechanisms ◽

Morphological Changes ◽

Osteosarcoma Cells ◽

Invasion And Metastasis ◽

Platelet Releasate

AbstractOsteosarcoma is the most common primary malignant bone cancer, with high rates of pulmonary metastasis. Osteosarcoma patients with pulmonary metastasis have worse prognosis than those with localized disease, leading to dramatically reduced survival rates. Therefore, understanding the biological characteristics of metastatic osteosarcoma and the molecular mechanisms of invasion and metastasis of osteosarcoma cells will lead to the development of innovative therapeutic intervention for advanced osteosarcoma. Here, we identified that osteosarcoma cells commonly exhibit high platelet activation-inducing characteristics, and molecules released from activated platelets promote the invasiveness of osteosarcoma cells. Given that heat-denatured platelet releasate maintained the ability to promote osteosarcoma invasion, we focused on heat-tolerant molecules, such as lipid mediators in the platelet releasate. Osteosarcoma-induced platelet activation leads to abundant lysophosphatidic acid (LPA) release. Exposure to LPA or platelet releasate induced morphological changes and increased invasiveness of osteosarcoma cells. By analyzing publicly available transcriptome datasets and our in-house osteosarcoma patient-derived xenograft tumors, we found that LPA receptor 1 (LPAR1) is notably upregulated in osteosarcoma. LPAR1 gene KO in osteosarcoma cells abolished the platelet-mediated osteosarcoma invasion in vitro and the formation of early pulmonary metastatic foci in experimental pulmonary metastasis models. Of note, the pharmacological inhibition of LPAR1 by the orally available LPAR1 antagonist, ONO-7300243, prevented pulmonary metastasis of osteosarcoma in the mouse models. These results indicate that the LPA–LPAR1 axis is essential for the osteosarcoma invasion and metastasis, and targeting LPAR1 would be a promising therapeutic intervention for advanced osteosarcoma.

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Topical cream optimization and in vitro testing of bromelain nanoemulsion from pineapple core as anti-inflammation agents

10.1063/5.0052799 ◽

2021 ◽

Author(s):

Denny J. Pasaribu ◽

Siswati Setiasih ◽

Sumi Hudiyono

Keyword(s):

In Vitro Testing ◽

Topical Cream ◽

Anti Inflammation

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MBRS-48. IDENTIFICATION OF NOVEL THERAPEUTIC APPROACHES FOR MYC-DRIVEN MEDULLOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa222.557 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii406-iii406

Author(s):

Kübra Taban ◽

David Pauck ◽

Mara Maue ◽

Viktoria Marquardt ◽

Hua Yu ◽

...

Keyword(s):

New Drugs ◽

Current Therapy ◽

Cancer Drug ◽

Mrna Levels ◽

Cell Models ◽

Therapeutic Approaches ◽

Group 3 ◽

Novel Therapeutic

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children and is frequently metastatic at diagnosis. Treatment with surgery, radiation and multi-agent chemotherapy may leave survivors of these brain tumors with long-term deficits as a consequence. One of the four consensus molecular subgroups of MB is the MYC-driven group 3 MB, which is the most malignant type and has a poor prognosis under current therapy. Thus, it is important to discover more effective targeted therapeutic approaches. We conducted a high-throughput drug screening to identify novel compounds showing efficiency in group 3 MB using both clinically established inhibitors (n=196) and clinically-applicable compounds (n=464). More than 20 compounds demonstrated a significantly higher anti-tumoral effect in MYChigh (n=7) compared to MYClow (n=4) MB cell models. Among these compounds, Navitoclax and Clofarabine showed the strongest effect in inducing cell cycle arrest and apoptosis in MYChigh MB models. Furthermore, we show that Navitoclax, an orally bioavailable and blood-brain barrier passing anti-cancer drug, inhibits specifically Bcl-xL proteins. In line, we found a significant correlation between BCL-xL and MYC mRNA levels in 763 primary MB patient samples (Data source: “R2 https://hgserver1.amc.nl”). In addition, Navitoclax and Clofarabine have been tested in cells obtained from MB patient-derived-xenografts, which confirmed their specific efficacy in MYChigh versus MYClow MB. In summary, our approach has identified promising new drugs that significantly reduce cell viability in MYChigh compared to MYClow MB cell models. Our findings point to novel therapeutic vulnerabilities for MB that need to be further validated in vitro and in vivo.

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In vitro testing of anthelmintic efficacy of Flemingia vestita (Fabaceae) on carbohydrate metabolism in Rallietina echinobothrida

Methods ◽

10.1016/j.ymeth.2007.01.005 ◽

2007 ◽

Vol 42 (4) ◽

pp. 330-338 ◽

Cited By ~ 16

Author(s):

V. Tandon ◽

B. Das

Keyword(s):

Carbohydrate Metabolism ◽

In Vitro Testing ◽

Anthelmintic Efficacy

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TNFα secreted by glioma associated macrophages promotes endothelial activation and resistance against anti-angiogenic therapy

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01163-0 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Qingxia Wei ◽

Olivia Singh ◽

Can Ekinci ◽

Jaspreet Gill ◽

Mira Li ◽

...

Keyword(s):

Critical Role ◽

Gene Expression Signature ◽

Endothelial Activation ◽

Tumor Vascularization ◽

Angiogenic Therapy ◽

Mouse Glioma ◽

Novel Therapeutic ◽

Tumor Area

AbstractOne of the most prominent features of glioblastoma (GBM) is hyper-vascularization. Bone marrow-derived macrophages are actively recruited to the tumor and referred to as glioma-associated macrophages (GAMs) which are thought to provide a critical role in tumor neo-vascularization. However, the mechanisms by which GAMs regulate endothelial cells (ECs) in the process of tumor vascularization and response to anti-angiogenic therapy (AATx) is not well-understood. Here we show that GBM cells secrete IL-8 and CCL2 which stimulate GAMs to produce TNFα. Subsequently, TNFα induces a distinct gene expression signature of activated ECs including VCAM-1, ICAM-1, CXCL5, and CXCL10. Inhibition of TNFα blocks GAM-induced EC activation both in vitro and in vivo and improve survival in mouse glioma models. Importantly we show that high TNFα expression predicts worse response to Bevacizumab in GBM patients. We further demonstrated in mouse model that treatment with B20.4.1.1, the mouse analog of Bevacizumab, increased macrophage recruitment to the tumor area and correlated with upregulated TNFα expression in GAMs and increased EC activation, which may be responsible for the failure of AATx in GBMs. These results suggest TNFα is a novel therapeutic that may reverse resistance to AATx. Future clinical studies should be aimed at inhibiting TNFα as a concurrent therapy in GBMs.

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In Vitro Testing of Antimicrobial Agents

Infectious Disease Clinics of North America ◽

10.1016/s0891-5520(20)30275-0 ◽

1989 ◽

Vol 3 (3) ◽

pp. 375-388

Author(s):

John A. Washington

Keyword(s):

Antimicrobial Agents ◽

In Vitro Testing

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The loss of SHMT2 mediates 5-fluorouracil chemoresistance in colorectal cancer by upregulating autophagy

Oncogene ◽

10.1038/s41388-021-01815-4 ◽

2021 ◽

Author(s):

Jian Chen ◽

Risi Na ◽

Chao Xiao ◽

Xiao Wang ◽

Yupeng Wang ◽

...

Keyword(s):

Colorectal Cancer ◽

Patient Survival ◽

Serine Hydroxymethyltransferase ◽

First Line ◽

Xenograft Models ◽

Potential Opportunity ◽

First Line Treatment ◽

Novel Therapeutic

Abstract5-Fluorouracil (5-FU)-based chemotherapy is the first-line treatment for colorectal cancer (CRC) but is hampered by chemoresistance. Despite its impact on patient survival, the mechanism underlying chemoresistance against 5-FU remains poorly understood. Here, we identified serine hydroxymethyltransferase-2 (SHMT2) as a critical regulator of 5-FU chemoresistance in CRC. SHMT2 inhibits autophagy by binding cytosolic p53 instead of metabolism. SHMT2 prevents cytosolic p53 degradation by inhibiting the binding of p53 and HDM2. Under 5-FU treatment, SHMT2 depletion promotes autophagy and inhibits apoptosis. Autophagy inhibitors decrease low SHMT2-induced 5-FU resistance in vitro and in vivo. Finally, the lethality of 5-FU treatment to CRC cells was enhanced by treatment with the autophagy inhibitor chloroquine in patient-derived and CRC cell xenograft models. Taken together, our findings indicate that autophagy induced by low SHMT2 levels mediates 5-FU resistance in CRC. These results reveal the SHMT2–p53 interaction as a novel therapeutic target and provide a potential opportunity to reduce chemoresistance.

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