Tumor-macrophage crosstalk: how to listen

2020 ◽  
Author(s):  
Tuli Dey
Keyword(s):  
Immune Response ◽  
Clinical Trials ◽  
Survival Analysis ◽  
Patient Survival ◽  
Model Systems ◽  
Potential Candidate ◽  
Suppression Of Immune Response ◽  
Cellular Components ◽  
Precision Therapeutics

Abstract The tumor microenvironment contains many cellular components influencing tumor behaviors, such as metastasis, angiogenesis and chemo-resistance. Tumor-associated macrophages (TAMs) are one of such components that can also manipulate the overall prognosis and patient survival. Analysis of tumor-macrophage crosstalk is crucial as tumor cells can polarize circulatory monocytes into TAMs. Such trans-polarization of macrophages support tumor mediated evasion and suppression of immune response. Additionally, such TAMs significantly influence tumor growth and proliferation, making them a potential candidate for precision therapeutics. However, the failure of macrophage-dependent therapies at clinical trials emphasizes the fault in current perception and research modality. This review discussed this field’s progress regarding emerging model systems with a focused view on the in vitro platforms. The inadequacy of currently available models and their implications on existing studies also analyzed. The need for a conceptual and experimental leap toward a human-relevant in vitro custom-built platform for studying tumor-macrophage crosstalk is acknowledged.

Combining galiximab with the chemotherapeutic agents fludarabine or doxorubicin improves efficacy in animal models of lymphoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3040-3040 ◽  
Author(s):  
H. K. Hariharan ◽  
T. Murphy ◽  
D. Clanton ◽  
L. Berquist ◽  
P. Chu ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Animal Models ◽  
Clinical Benefit ◽  
Therapeutic Potential ◽  
Xenograft Model ◽  
Chemotherapeutic Agents ◽  
Model Systems ◽  
Anti Cd20

3040 Background: Galiximab, a primatized monoclonal antibody that binds with high affinity to CD80 and mediates antibody- dependent, cell-mediated cytotoxicity in vitro, is currently under investigation for the treatment of follicular non-Hodgkin’s lymphoma (NHL). In a phase I/II monotherapy study, galiximab produced an overall response rate of 11%, and tumor reductions were observed in 46% of patients. Initial clinical trials also demonstrate that galiximab is well tolerated and suggest that combining galiximab with rituximab (anti-CD20) provides clinical benefit. These results are consistent with preclinical studies in murine lymphoma xenograft model systems, which demonstrate the superiority of combination therapy. Methods: To further define the therapeutic potential of galiximab, the Raji subcutaneous and the SKW disseminated lymphoma murine xenograft models were used to define the in vivo efficacy of galiximab alone or in combination with fludarabine or doxorubicin. Similar studies were performed with rituximab. Results: In the Raji model, both galiximab and rituximab exhibited maximal inhibition of the growth of preestablished (150-mg) tumors at a dose of 3 mg/kg/wk. Interestingly, higher doses of galiximab (but not rituximab) showed reduced inhibition. Galiximab (3 mg/kg/wk) inhibited tumor growth alone (P<0.0001 vs. control) and showed significantly enhanced activity when combined with fludarabine (50 or 100 mg/kg daily for 5 days; P<0.0002 vs. galiximab alone and P<0.003 vs. fludarabine alone). Similar results were observed with rituximab. In the SKW model, treatment with galiximab (5 mg/kg/wk for 6 doses) significantly enhanced survival compared with a control (P<0.0001) or doxorubicin (2.5 mg/kg/day for 3 doses; P<0.0001). Studies combining fludarabine or doxorubicin with both galiximab and rituximab are ongoing. Conclusions: Studies in animal models of lymphoma indicate that galiximab may provide clinical benefit when used in combination with chemotherapeutic agents such as fludarabine and doxorubicin, and provide a rationale for the investigation of these novel chemoimmunotherapy combinations in clinical trials. No significant financial relationships to disclose.

scholarly journals Pharmacological effects of saffron and its constituents in ocular disorders from in vitro studies to clinical trials; a systematic review

2020 ◽  
Vol 18 ◽  
Author(s):  
Samaneh Sepahi ◽  
Adel Ghorani-Azam ◽  
Seyedeh Maryam Hossieni ◽  
Seyed Ahmad Mohajeri ◽  
Elham Khodavrdi
Keyword(s):  
Clinical Trials ◽  
Clinical Studies ◽  
Therapeutic Potential ◽  
In Vitro Studies ◽  
Therapeutic Effects ◽  
Potential Candidate ◽  
Retinal Cells ◽  
Age Related ◽  
Eye Disorders

Introduction: Some medicinal plants have shown promising therapeutic potential for management of the diseases. We aimed to systematically review the literature wherein the therapeutic effects of saffron have been studied on eye disorders. Methods: A systematic literature search was performed in PubMed, Scopus, Web of Science, Google scholar and other databases using eye disorders, and saffron as key terms. No strict inclusion criteria were defined, and almost all clinical studies, as well as in vivo and in vitro studies were included. The reported data in each study were extracted and then qualitatively described. Results: Finally, 78 articles were found but only 29 relevant articles were included. Nine articles are clinical trials and 20 articles were done on cellular and molecular aspects of saffron on eye disorders. According to the included studies, crocin prevented the pro-inflammatory response in retinal cells and decreased glucose level in diabetic mice. Also, crocetin prevented retinal degeneration and saffron protected photoreceptors from light-induced damage in retinal cells. Saffron also improved visual function in age-related macular edema and decreased intraocular pressure in patients with glaucoma. In addition, it was shown that crocin can improve best corrected visual acuity and decreased central macular thickness in patients with diabetic maculopathy. Conclusion: The results of this review indicated that saffron and its main ingredients such as crocin could be a potential candidate for the treatment of ocular disease especially eye inflammation; however, further clinical studies are needed to confirm such efficiency.

scholarly journals Immunomodulatory Effects of Adipose-Derived Stem Cells: Fact or Fiction?

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Angelo A. Leto Barone ◽  
Saami Khalifian ◽  
W. P. Andrew Lee ◽  
Gerald Brandacher
Keyword(s):  
Stem Cells ◽  
Immune Response ◽  
Clinical Trials ◽  
Immune System ◽  
Solid Organ ◽  
Adipose Derived Stem Cells ◽  
Adipose Derived Stromal Cells

Adipose-derived stromal cells (ASCs) are often referred to as adipose-derived stem cells due to their potential to undergo multilineage differentiation. Their promising role in tissue engineering and ability to modulate the immune system are the focus of extensive research. A number of clinical trials using ASCs are currently underway to better understand the role of such cell niche in enhancing or suppressing the immune response. If governable, such immunoregulatory role would find application in several conditions in which an immune response is present (i.e., autoimmune conditions) or feared (i.e., solid organ or reconstructive transplantation). Although allogeneic ASCs have been shown to prevent acute GvHD in both preclinical and clinical studies, their potential warrants further investigation. Well-designed and standardized clinical trials are necessary to prove the role of ASCs in the treatment of immune disorders or prevention of tissue rejection. In this paper we analyze the current literature on the role of ASCs in immunomodulationin vitroandin vivoand discuss their potential in regulating the immune system in the context of transplantation.

scholarly journals Live-imaging rate-of-kill compound profiling for Chagas disease drug discovery with a new automated high-content assay

2021 ◽  
Vol 15 (10) ◽  
pp. e0009870
Author(s):  
Nina Svensen ◽  
Susan Wyllie ◽  
David W. Gray ◽  
Manu De Rycker
Keyword(s):  
Clinical Trials ◽  
Chagas Disease ◽  
Time Resolution ◽  
Standard Of Care ◽  
Live Imaging ◽  
Model Systems ◽  
High Time Resolution ◽  
Laboratory Findings

Chagas disease, caused by the protozoan intracellular parasite Trypanosoma cruzi, is a highly neglected tropical disease, causing significant morbidity and mortality in central and south America. Current treatments are inadequate, and recent clinical trials of drugs inhibiting CYP51 have failed, exposing a lack of understanding of how to translate laboratory findings to the clinic. Following these failures many new model systems have been developed, both in vitro and in vivo, that provide improved understanding of the causes for clinical trial failures. Amongst these are in vitro rate-of-kill (RoK) assays that reveal how fast compounds kill intracellular parasites. Such assays have shown clear distinctions between the compounds that failed in clinical trials and the standard of care. However, the published RoK assays have some key drawbacks, including low time-resolution and inability to track the same cell population over time. Here, we present a new, live-imaging RoK assay for intracellular T. cruzi that overcomes these issues. We show that the assay is highly reproducible and report high time-resolution RoK data for key clinical compounds as well as new chemical entities. The data generated by this assay allow fast acting compounds to be prioritised for progression, the fate of individual parasites to be tracked, shifts of mode-of-action within series to be monitored, better PKPD modelling and selection of suitable partners for combination therapy.

Production of immune response mediators by HT-29 intestinal cell-lines in the presence of Bifidobacterium-treated infant microbiota

2015 ◽  
Vol 6 (4) ◽  
pp. 543-552 ◽  
Author(s):  
S. Arboleya ◽  
B. Bahrami ◽  
S. Macfarlane ◽  
M. Gueimonde ◽  
G.T. Macfarlane ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Intestinal Microbiota ◽  
Short Chain Fatty Acids ◽  
Model Systems ◽  
Intestinal Cell ◽  
Intestinal Cells ◽  
Suitable Model ◽  
Ht 29

The colonisation and establishment of the intestinal microbiota starts immediately at birth and is essential for the development of the intestine and the immune system. This microbial community gradually increases in number and diversity until the age of two or three years when it becomes a stable ecosystem resembling that of adults. This period constitutes a unique window of opportunity to modulate it through probiotic action, with a potential impact in later health. In the present work we have investigated how putative bifidobacterial probiotics modify the metabolic profiles and immune-modulatory properties of faecal microbiotas. An in vitro pH-controlled single-stage continuous-culture system (CCS) inoculated with infant faeces was employed to characterise the effects of two Bifidobacterium species on the intestinal microbiotas in three children, together with the effects of these modified microbiotas on cytokine production by HT-29 cells. Intestinal bacterial communities, production of short-chain fatty acids and lactate were determined by quantitative PCR and gas chromatography, respectively. Cytokines production by HT-29 cells was measured by ELISA. The combination of CCS with infant faeces and human intestinal cells provided a suitable model to evaluate the specific modulation of the intestinal microbiota and immune system by probiotics. In the CCS, infant faecal microbiotas were influenced by the addition of bifidobacteria, resulting in changes in their ability to induce the production of immune mediators by HT-29 cells. The different metabolic and immunological responses induced by the bifidobacterial species tested indicate the need to assess potential probiotics in model systems including complex intestinal microbiotas. Potential probiotic bifidobacteria can modulate the infant microbiota and its ability to induce the production of mediators of the immune response by intestinal cells.

scholarly journals Differential mRNA and miRNA Profiles Reveal the Potential Roles of Genes and miRNAs Involved in LPS Infection in Chicken Macrophages

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 760
Author(s):  
Qi Zhang ◽  
Jie Wang ◽  
Jin Zhang ◽  
Jie Wen ◽  
Guiping Zhao ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Immune Response ◽  
Target Genes ◽  
Differentially Expressed ◽  
Gram Negative Bacteria ◽  
Potential Candidate ◽  
Gram Negative ◽  
Immune Related Genes

Lipopolysaccharide (LPS) is a component of the cell wall of Gram-negative bacteria, and triggers an inflammatory response both in vitro and in vivo. Here, we used LPS from Escherichia coli serotype enteritidis to stimulate chicken macrophages (HD11) and conducted the transcriptome analysis using a bioinformatics approach to explore the functions of immune-related genes and miRNAs. In total, 1759 differentially expressed genes (DEGs) and 18 differentially expressed (DE)-miRNAs were detected during LPS infection. At 6 h post infection, 1025 DEGs and 10 miRNAs were up-regulated, and 734 DEGs and 8 DE-miRNAs were down-regulated. Based on both RNA hybrid and miRanda systems, 55 DEGs could be targeted by 14 DE-miRNAs. The target genes were related to the immune response, such as IRF8, STAT3, TRAF7, and other potential candidate genes. The DE-miRNAs miR146a-3p, miR6583-5p, and miR30c-2-3p were investigated further. They were predicted to target 34 genes that may also be candidates for immune-related miRNAs and genes. Our results enhanced our understanding of the pathogenic mechanisms of Gram-negative bacteria in chickens.

Gender-Based Differences in the Toxicity of Pharmaceuticals—The Food and Drug Administration's Perspective

2001 ◽  
Vol 20 (3) ◽  
pp. 149-152 ◽  
Author(s):  
Margaret Ann Miller
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Sex Difference ◽  
Qt Interval ◽  
Drug Effects ◽  
Drug Efficacy ◽  
Model Systems ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Drug Induced

Women experience more adverse reactions to treatment with therapeutic drugs than men. Theories proposed to explain this include overdosing, different pharmacokinetics and pharmacodynamics, women are more likely to report adverse events than men, or women take more medications than men. Food and Drug Administration (FDA) Office of Women's Health (OWH) funds research to promote including women in clinical trials and understanding the biology of sex-related differences in the safety of FDA-regulated products. Including women in clinical trials advances the understanding of drug efficacy and safety in women by providing information on drug dosing, pharmacokinetics, and pharmacodynamics. A Baysian statistical analysis of sex differences in adverse events showed that although about the same number of adverse events were reported for men and women, those reported for women were more serious. One example of a sex difference in the toxicity of pharmaceuticals is the drug-induced cardiac arrhythmia, torsades de point. OWH funded studies in animals and humans to investigate the mechanism behind this sex difference. These studies demonstrated that shortening the QT interval increases the risk of developing torsades and that androgens protect against torsades by slowing cardiac repolarization and prolonging the QT interval. Understanding the mechanisms behind other reported sex-related differences in adverse drug effects requires additional research. The preliminary studies conducted to date suggest that this sex-related difference is likely to be a multifactorial problem requiring information from several fields of study. Ideally, individuals at risk for developing an adverse event should be identified prior to therapeutic intervention. The OWH plans to fund more studies to investigate the role of hormonal variations on drug metabolism and drug-drug interactions. Animal and in vitro model systems are needed to fully understand the mechanism of how gender influences drug toxicity.

scholarly journals Enhancing Natural Product Clinical Trials (P13-037-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Barbara Sorkin ◽  
Adam Kuszak ◽  
Guido Pauli ◽  
Gregory Bloss ◽  
Bruce Barrett ◽  
...  
Keyword(s):  
Public Health ◽  
Clinical Trials ◽  
Natural Product ◽  
Null Hypothesis ◽  
Protein Denaturation ◽  
Model Systems ◽  
Vitro Assay ◽  
Good Practices ◽  
Product Identity

Abstract Objectives To discuss good practices and criteria for optimal design and interpretation of pre-clinical and clinical natural product (NP) research in order to increase benefit from our investment in NP clinical trials (CT). Background: Large, randomized, controlled CT often fail to reject the null hypothesis or show rigorous evidence of benefit. This includes recent large, NIH-supported CT of nutrients such as vitamin D and selenium, and of botanical dietary supplements. Negative and positive outcomes may be equally important for public health, but because large CT cost at least $20 M each, plus opportunity costs, it is important that CT designs maximize the yield of actionable information regardless of outcome. Methods Experts and stakeholders from academia, government and the private sector collaboratively developed a broadly attended workshop in which good practices to enhance rigor, reproducibility and translational relevance were discussed. Results N/A. Conclusions Critical issues in CT design include product identity, reproducibility and pharmacology (where feasible), power to test a primary outcome significant to consumers, and placebo controls. When basing a CT on traditional use or prior in vitro or in vivo studies, similarity of product (e.g., source identity, methods of preparation, form and intake), health outcome and population (e.g., age, sex, genetics, diet and environment), require careful consideration. Appropriate controls for known types of in vitro assay interference (e.g., aggregation, membrane disruption, protein denaturation) are imperative. Compounds with limited bioavailability, or activity only at concentrations above those achievable by ingestion, are likely poor candidates for dietary CT. Translational validity of model systems should be carefully assessed. Appropriate analyses (e.g., p-curve and meta-regression methods) should be used to obtain bias-corrected effect size estimates, and to identify research areas where the evidence base may be weaker than published findings suggest. Finally, CT prioritization should consider expected impact on public health, and whether known NP causal mechanisms of action are such that useful information, e.g., on product bioavailability or biological activity, are generated even if the completed CT fails to reject the null hypothesis. Funding Sources NIH, FDA, USDA.

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