Panel Discussion II: Usefulness of in vitro and in vivo Model Systems for Predicting the Adverse Public Health Outcome for Antimicrobial Drug Residues in Food

Obesity has been linked to more aggressive characteristics of several cancers, including breast and prostate cancer. Adipose tissue appears to contribute to paracrine interactions in the tumor microenvironment. In particular, cancer-associated adipocytes interact reciprocally with cancer cells and influence cancer progression. Adipokines secreted from adipocytes likely form a key component of the paracrine signaling in the tumor microenvironment. In vitro coculture models allow for the assessment of specific adipokines in this interaction. Furthermore, micronutrients and macronutrients present in the diet may alter the secretion of adipokines from adipocytes. The effect of dietary fat and specific fatty acids on cancer progression in several in vivo model systems and cancer types is reviewed. The more common approaches of caloric restriction or diet-induced obesity in animal models establish that such dietary changes modulate tumor biology. This review seeks to explore available evidence regarding how diet may modulate tumor characteristics through changes in the role of adipocytes in the tumor microenvironment.

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In Vitro and In Vivo Model Systems of Cholangiocarcinoma

Diagnosis and Management of Cholangiocarcinoma ◽

10.1007/978-3-030-70936-5_22 ◽

2021 ◽

pp. 471-494

Author(s):

Giovanni Brandi ◽

Simona Tavolari

Keyword(s):

Model Systems ◽

In Vivo Model

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Unbiased in vivo preclinical evaluation of anticancer drugs identifies effective therapy for the treatment of pancreatic adenocarcinoma

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1920240117 ◽

2020 ◽

Vol 117 (48) ◽

pp. 30670-30678

Author(s):

Olivera Grbovic-Huezo ◽

Kenneth L. Pitter ◽

Nicolas Lecomte ◽

Joseph Saglimbeni ◽

Gokce Askan ◽

...

Keyword(s):

Large Scale ◽

Single Agent ◽

Model Systems ◽

Ductal Adenocarcinoma ◽

In Vivo Model ◽

Cancer Therapies ◽

Hsp90 Inhibition ◽

Dismal Prognosis

Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at an advanced stage, which limits surgical options and portends a dismal prognosis. Current oncologic PDAC therapies confer marginal benefit and, thus, a significant unmet clinical need exists for new therapeutic strategies. To identify effective PDAC therapies, we leveraged a syngeneic orthotopic PDAC transplant mouse model to perform a large-scale, in vivo screen of 16 single-agent and 41 two-drug targeted therapy combinations in mice. Among 57 drug conditions screened, combined inhibition of heat shock protein (Hsp)-90 and MEK was found to produce robust suppression of tumor growth, leading to an 80% increase in the survival of PDAC-bearing mice with no significant toxicity. Mechanistically, we observed that single-agent MEK inhibition led to compensatory activation of resistance pathways, including components of the PI3K/AKT/mTOR signaling axis, which was overcome with the addition of HSP90 inhibition. The combination of HSP90(i) + MEK(i) was also active in vitro in established human PDAC cell lines and in vivo in patient-derived organoid PDAC transplant models. These findings encourage the clinical development of HSP90(i) + MEK(i) combination therapy and highlight the power of clinically relevant in vivo model systems for identifying cancer therapies.

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Monoclonal and Single Domain Antibodies Targeting β-Integrin Subunits Block Sexual Transmission of HIV-1 in In Vitro and In Vivo Model Systems

JAIDS Journal of Acquired Immune Deficiency Syndromes ◽

10.1097/qai.0000000000000609 ◽

2015 ◽

Vol 69 (3) ◽

pp. 278-285 ◽

Cited By ~ 4

Author(s):

Janet Tai Guedon ◽

Kun Luo ◽

Hong Zhang ◽

Richard B. Markham

Keyword(s):

Sexual Transmission ◽

Single Domain ◽

Model Systems ◽

In Vivo Model ◽

Single Domain Antibodies ◽

Sexual Transmission Of Hiv ◽

Hiv 1

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ENHANCED FLUORESCENCE IMAGING WITH DMSO-MEDIATED OPTICAL CLEARING

Journal of Innovative Optical Health Sciences ◽

10.1142/s1793545810001015 ◽

2010 ◽

Vol 03 (03) ◽

pp. 153-158 ◽

Cited By ~ 10

Author(s):

SANJEEV KARMA ◽

JAMES HOMAN ◽

CHARLES STOIANOVICI ◽

BERNARD CHOI

Keyword(s):

Fluorescence Emission ◽

Model Systems ◽

In Vivo Studies ◽

In Vivo Model ◽

Fluorescence Signal ◽

Optical Clearing ◽

Treated Site

Recent studies have demonstrated that topical application of glycerol on intact skin does not affect its optical scattering properties. Investigators from our research group recently revisited the use of dimethyl sulfoxide (DMSO) as an agent with optical clearing potential. We address the use of optical clearing to enhance quantitation of subsurface fluorescence emission. We employed both in vitro and in vivo model systems to study the effect of topical DMSO application on fluorescence emission. Our in vitro experiments performed on a tissue-simulating phantom suggest that DMSO-mediated optical clearing enables enhanced characterization of subsurface fluorophores. With topical DMSO application, a marked increase in fluorescence emission was observed. After 30 min, the fluorescence signal at the DMSO-treated site was 9× greater than the contralateral saline-treated site. This ratio increased to 13× at 105 min after agent application. In summary, DMSO is an effective optical clearing agent for improved fluorescence emission quantitation and warrants further study in preclinical in vivo studies. Based on outcomes from previous clinical studies on the toxicity profile of DMSO, we postulate that clinical application of DMSO as an optical clearing agent, can be performed safely, although further study is warranted.

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De novo disease-associated mutations in KIF1A dominant negatively inhibit axonal transport of synaptic vesicle precursors

10.1101/2021.07.22.453457 ◽

2021 ◽

Author(s):

Yuzu Anazawa ◽

Tomoki Kita ◽

Kumiko Hayashi ◽

Shinsuke Niwa

Keyword(s):

Synaptic Vesicle ◽

Axonal Transport ◽

De Novo ◽

Molecular Motor ◽

Model Systems ◽

In Vitro Assays ◽

In Vivo Model ◽

Wild Type

KIF1A is a kinesin superfamily molecular motor that transports synaptic vesicle precursors in axons. Mutations in Kif1a lead to a group of neuronal diseases called KIF1A-associated neuronal disorder (KAND). KIF1A forms a homodimer and KAND mutations are mostly de novo and autosomal dominant; however, it is not known whether the function of wild-type KIF1A is inhibited by disease-associated KIF1A. No reliable in vivo model systems to analyze the molecular and cellular biology of KAND have been developed; therefore, here, we established Caenorhabditis elegans models for KAND using CRISPR/cas9 technology and analyzed defects in axonal transport. In the C. elegans models, heterozygotes and homozygotes exhibited reduced axonal transport phenotypes. In addition, we developed in vitro assays to analyze the motility of single heterodimers composed of wild-type KIF1A and disease-associated KIF1A. Disease-associated KIF1A significantly inhibited the motility of wild-type KIF1A when heterodimers were formed. These data indicate the molecular mechanism underlying the dominant nature of de novo KAND mutations.

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DNA sequencing of the small bowel adenocarcinomas to identify targetable ErbB2 mutations.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15800 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15800-e15800

Author(s):

Liana Adam ◽

Jerry Fowler ◽

Wenhui Wu ◽

Yao Yu ◽

Huamin Wang ◽

...

Keyword(s):

Small Bowel ◽

Cell Lines ◽

Somatic Mutations ◽

Genetic Alterations ◽

Model Systems ◽

Parp Cleavage ◽

In Vivo Model ◽

Small Bowel Adenocarcinoma

e15800 Background: Small bowel adenocarcinoma (SBA) is a rare malignancy of the digestive tract with limited knowledge about its genetic alterations. Methods: Eighteen tumor and normal matched samples were sequenced using the whole-exome-Illumina platform. Various agnostic analysis methods were used to identify relevant somatic mutations and the results were compared with the available TCGA datasets. To test potential targetable mutations we developed eight patient-derived xenografts (PDX) and three cell lines from freshly-collected primary or metastatic SBA tissues. Two kinase-activating ErbB2 mutations (V842I and Y803H) and one wild-type (wt) ErbB2 (n = 30) PDX models were used to measure the effect of Dacomitinib (Daco) on tumor growth. ErbB2-mutant tumor-derived cell lines were tested for Daco and Lapatinib (Lapa) response in-vitro. Reverse-phase-protein-arrays (RPPA) were used to identify molecular changes. Results: Several unexpected oncogenic mechanisms were suggested by the pattern of somatic mutations across the dataset, including mutations in the Notch and Hippo pathways. In addition, we found 6/18 APC truncating mutations exclusive to mutations in ZNRF3 or RNF43 genes, suggesting that non-APC wnt-activating mechanisms are important in SBA, while considered a minority in CRC. Importantly, 6/18 samples displayed ErbB2 mutations, of which 4 resided in the kinase domain, D769Y, V777L, Y803H and V842I. Nanomolar doses of both Lapa and Daco significantly inhibited ErbB2-mutants’ cell proliferation in-vitro. Target inhibition was confirmed by the RPPA results: EGFR-Y1068, ErbB2-Y1248 and PKCα-S657 dephosphorylation, PCNA reduction and PARP cleavage increase. In-vivo-administered Daco resulted in significant tumor reduction in ErbB2-V841I (39%, p = 0.03) and ErbB2-Y803H (59%, p = 0.03) tumors, and had no anti-tumor effect on wt-ErbB2 tumors. Conclusions: The generation of in-vitro and in-vivo model systems from rare cancers is possible and provides a valuable resource into understanding potentially relevant targetable mutations. Our findings suggest that SBA patients with ErbB2-activating mutations should be considered for clinical trials targeting this alteration.

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