Animal Tumor Research Articles

Molecular Identity Changes of Tumor-Associated Macrophages and Microglia After Magnetic Resonance Imaging-Guided Focused Ultrasound-Induced Blood-Brain Barrier Opening in a Mouse Glioblastoma Model.

An orthotopically allografted mouse GL26 glioma model (Ccr2RFP/wt-Cx3cr1GFP/wt) was used to evaluate the effect of transient, focal opening of the blood-brain barrier (BBB) on the composition of tumor-associated macrophages and microglia (TAMs). BBB opening was induced by magnetic resonance imaging (MRI)-guided focused ultrasound (MRgFUS) combined with microbubbles. CX3CR1-GFP cells and CCR2-RFP cells in brain tumors were quantified in microscopic images. Tumors in animals treated with a single session of MRgFUS did not exhibit significant changes in cell numbers when compared with tumors in animals not receiving FUS. However, tumors that received two or three sessions of MRgFUS had significantly increased amounts of both CX3CR1-GFP and CCR2-RFP cells. The effect of MRgFUS on immune cell composition was also characterized and quantified using flow cytometry. Glioma implantation resulted in increased amounts of lymphocytes, monocytes and neutrophils in the brain parenchyma. Tumors administered MRgFUS exhibited increased numbers of monocytes and monocyte-derived TAMs. In addition, MRgFUS-treated tumors exhibited more CD80+ cells in monocytes and microglia. In summary, transient, focal opening of the BBB using MRgFUS combined with microbubbles can activate the homing and differentiation of monocytes and induce a shift toward a more pro-inflammatory status of the immune environment in glioblastoma.

Immunohistochemical evaluation of cellular activities in canine osteoblastic osteosarcoma

Osteosarcoma is the most frequently occurring malignant bone tumor in animals and humans. A better understanding of the etiopathogenetic mechanisms of osteosarcoma, especially biomolecular ones, is fundamental to improving diagnosis and prognosis of the disease. Autophagy is a self-degrative process that removes dysfunctional cellular components, eliminates intracellular pathogens, and promotes cellular senescence. In neoplastic cells, autophagy suppresses tumorigenesis by inhibiting cancer cell survival mechanisms and promoting cell death. The aim of this study was to use immunohistochemistry to identify alterations in the expression of several apoptotic and proliferative biomarkers in multiple cases of canine osteosarcoma. Bcl-2, an intracellular membrane protein, inhibits cell death by blocking the p53-mediated pathway of apoptosis. While Bcl-2 overexpression has been described in many different premalignant and malignant lesions, it has yet to be analyzed in canine osteosarcoma. Our group investigated 10 primary canine osteoblastic osteosarcoma cases from the University of Perugia Department of Veterinary Medicine Teaching Hospital. Immunohistochemical analyses of proteins Bcl-2, Ki-67, and p53 have revealed interesting results as described in this paper. Expression of Bcl-2 was increased in all cases investigated while expression of p53 and Ki-67 was variable and no statistical association was observed between the expression patterns of p53, Bcl-2 and Ki-67.

Potential Effects of Geraniol on Cancer and Inflammation-Related Diseases: A Review of the Recent Research Findings.

Geraniol (GNL), a natural monoterpene, is found in many essential oils of fruits, vegetables, and herbs, including lavender, citronella, lemongrass, and other medicinal and aromatic plants. GNL is commonly used by the cosmetic and food industries and has shown a wide spectrum of pharmacological activities including anti-inflammatory, anticancer, antimicrobial, antioxidant, and neuroprotective activities. It represents a potential anti-inflammatory agent and a promising cancer chemopreventive agent, as it has been found to be effective against a broad range of cancers, including colon, prostate, breast, lung, skin, kidney, liver, and pancreatic cancer. Moreover, GNL scavenges free radicals and preserves the activity of antioxidant enzymes. In addition, GNL induces apoptosis and cell cycle arrest, modulates multiple molecular targets, including p53 and STAT3, activates caspases, and modulates inflammation via transcriptional regulation. In the present study, different modes of action are described for GNL's activity against cancer and inflammatory diseases. This compound protects various antioxidant enzymes, such as catalase, glutathione-S-transferase, and glutathione peroxidase. Experiments using allergic encephalomyelitis, diabetes, asthma, and carcinogenesis models showed that GNL treatment had beneficial effects with low toxicity. GNL has been shown to be effective in animal models and tumor cell lines, but there have not been any clinical studies carried out for it. The aim of the present review is to provide updated data on the potential effects of GNL on cancer and inflammation, and to enhance our understanding of molecular targets, involved pathways, and the possible use of GNL for clinical studies and therapeutic purposes in the treatment of cancer and inflammation-related diseases.

Abstract LB273: An emerging paradigm of heterogeneous midkine expression in thyroid cancer

Abstract Midkine (MDK) is a pleiotropic heparin-binding growth factor, contributing to both normal tissue homeostasis and disease development. MDK expression is gradually increased during carcinogenesis, acting as a mediator for the acquisition of cancer hallmarks, such as invasion/metastasis, and immunosuppression. Tissue-wide gene expression analysis using publicly available databases reveal that MDK is significantly upregulated in most human carcinomas. In the thyroid, MDK has been associated with increased metastatic potential in the context of papillary thyroid cancer, which is an otherwise relatively non-aggressive thyroid tumor. We thus theorized that more aggressive types of thyroid cancers may be linked to increased MDK expression/function from an earlier onset. To gain such insights, we developed a digital pathology infrastructure to investigate MDK expression in a characterized mouse model of Anaplastic Thyroid Carcinoma (ATC), the most aggressive and lethal type of thyroid cancer with low but increased prevalence in the human population, and an intrinsic resistance to available therapeutic options. Mice with conditional ablation of tumor suppressors, Pten and p53, in thyrocytes [Pten, p53]thyr-/− develop thyroid carcinomas with mixed follicular and anaplastic components, and histological hallmarks of high aggressiveness, including giant cells, bone metaplasia, and muscular/tracheal invasion, which are all recapitulated in human disease. MDK was more highly expressed in anaplastic, when compared to follicular components of the same animal tumors. When the above hallmarks were topographically and microanatomically demarcated within the anaplastic component, it was found that MDK expression was higher near and around giant cell islets, as well as within the anaplastic lesions invading beyond the cartilaginous rings of tracheal mucosal epithelium. Based on recent evidence that MDK does not solely function in the extracellular space, but can also be endocytosed within tumor cells, whereby it exerts tumor-promoting functions, we further quantified the intra/extranuclear MDK fraction using intensity thresholding immunofluorescence. Of interest, MDK+ follicular lesions, were primarily characterized by nuclear MDK expression, whereas MDK was mostly found secreted in the extracellular space of anaplastic lesions, thus implying different modes of MDK trafficking, secretion, and possibly function in them. The take home message is to work towards establishing and developing gain- and loss-of-function experiments, to elucidate mechanistic underpinnings on the role of MDK in the development of aggressive ATC lesions. Citation Format: Dimitra P. Anastasiadou, Antonio Di Cristofano, George S. Karagiannis. An emerging paradigm of heterogeneous midkine expression in thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB273.

Type 1 interferon mediated signaling is indispensable for eliciting anti-tumor responses by Mycobacterium indicus pranii.

The evolving tumor secretes various immunosuppressive factors that reprogram the tumor microenvironment (TME) to become immunologically cold. Consequently, various immunosuppressive cells like Tregs are recruited into the TME which in turn subverts the anti-tumor response of dendritic cells and T cells.Tumor immunotherapy is a popular means to rejuvenate the immunologically cold TME into hot. Mycobacterium indicus pranii (MIP) has shown strong immunomodulatory activity in different animal and human tumor models and has been approved for treatment of lung cancer (NSCLC) patients as an adjunct therapy. Previously, MIP has shown TLR2/9 mediated activation of antigen presenting cells/Th1 cells and their enhanced infiltration in mouse melanoma but the underlying mechanism by which it is modulating these immune cells is not yet known. This study reports for the first time that MIP immunotherapy involves type 1 interferon (IFN) signaling as one of the major signaling pathways to mediate the antitumor responses. Further, it was observed that MIP therapy significantly influenced frequency and activation of different subsets of T cells like regulatory T cells (Tregs) and CD8+ T cells in the TME. It reduces the migration of Tregs into the TME by suppressing the expression of CCL22, a Treg recruiting chemokine on DCs and this process is dependent on type 1 IFN. Simultaneously, in a type 1 IFN dependent pathway, it enhances the activation and effector function of the immunosuppressive tumor resident DCs which in turn effectively induce the proliferation and effector function of the CD8+ T cells. This study also provides evidence that MIP induced pro-inflammatory responses including induction of effector function of conventional dendritic cells and CD8+ T cells along with reduction of intratumoral Treg frequency are essentially mediated in a type 1 IFN-dependent pathway.

Fluorescence Lifetime Macro Imager for Biomedical Applications

This paper presents a new photoluminescence lifetime imager designed to map the molecular oxygen (O2) concentration in different phosphorescent samples ranging from solid-state, O2-sensitive coatings to live animal tissue samples stained with soluble O2-sensitive probes. In particular, the nanoparticle-based near-infrared probe NanO2-IR, which is excitable with a 625 nm light-emitting diode (LED) and emits at 760 nm, was used. The imaging system is based on the Timepix3 camera (Tpx3Cam) and the opto-mechanical adaptor, which also houses an image intensifier. O2 phosphorescence lifetime imaging microscopy (PLIM) is commonly required for various studies, but current platforms have limitations in their accuracy, general flexibility, and usability. The system presented here is a fast and highly sensitive imager, which is built on an integrated optical sensor and readout chip module, Tpx3Cam. It is shown to produce high-intensity phosphorescence signals and stable lifetime values from surface-stained intestinal tissue samples or intraluminally stained fragments of the large intestine and allows the detailed mapping of tissue O2 levels in about 20 s or less. Initial experiments on the imaging of hypoxia in grafted tumors in unconscious animals are also presented. We also describe how the imager can be re-configured for use with O2-sensitive materials based on Pt-porphyrin dyes using a 390 nm LED for the excitation and a bandpass 650 nm filter for emission. Overall, the PLIM imager was found to produce accurate quantitative measurements of lifetime values for the probes used and respective two-dimensional maps of the O2 concentration. It is also useful for the metabolic imaging of ex vivo tissue models and live animals.

Heterologous prime-boost vaccine using antigen-loaded microparticles and adenovirus (encoding antigen) enhances cellular immune responses and antitumor activity

Heterologous prime-boost vaccines have the potential to promote higher immune responses than homologous prime-boost vaccines and were used in this murine study to investigate the effect on the magnitude of the cellular (and humoral) antigen-specific immune responses and antitumor efficacy when a microparticle formulation (prime) is combined with an adenoviral vaccine (boost). Specifically, the prime comprised chick egg ovalbumin (OVA; 25 µg/dose), used here as a model tumor antigen (TA), encapsulated in microparticles (∼700 nm diameter) made from the biodegradable polymer, 50:50 poly(lactic-co-glycolic acid) (PLGA); while attenuated adenovirus (type 5) encoding OVA (Ad5OVA; 108 PFU/dose) was employed as the boost. The ability of OVA-loaded microparticles to enhance OVA-specific antibody responses, OVA-specific CD3 + CD8 + T cell responses and antitumor activity (i.e., protection against OVA-expressing tumor-challenge) to the heterologous prime-boost vaccine was investigated; and it was found that this prime-boost combination could significantly enhance OVA-specific cellular responses compared to all other vaccination groups and was the only group to confer a significant survival advantage over the unvaccinated group (naïve) in a prophylactic animal tumor model. This finding illustrates the potential for combining TA-loaded PLGA-based microparticles with other vaccine formats to improve tumor-specific cellular immune responses.

Abstract 5801: Inhibition of muscarinic acetylcholine receptors in glioma stem cells blocks tumor progression

Abstract Primary gliomas arising within the brain are the deadliest form of brain cancer and account for 78% of all malignant brain tumors. Glioma patients have a 5 percent five-year survival rate and drug-resistant tumors often recur following surgical resection and treatment with radiation and/or chemotherapy. The cancer stem cell hypothesis suggests the presence of a subset of undifferentiated cells, namely glioma stem cells (GSCs), in the heterogenous tumor mass responsible for disease progression. Understanding mechanisms responsible for maintaining GSCs and developing strategies to deplete the GSC population could improve glioma treatment and prognosis. Some GSCs are similar to oligodendrocyte precursor cells (OPCs), which are observed in neural development and the adult brain. OPCs are prone to malignant transformation and are believed to be a cell of origin for glioma. Recent findings indicate that the well-characterized neurotransmitter acetylcholine (ACh) maintains the primitive state of normal OPCs via muscarinic ACh receptors (mAChRs) preventing maturation and cell cycle exit. We hypothesized that cholinergic signaling may also maintain the primitive state of OPC-like GSCs. We analyzed publicly available single nuclei RNASeq data of patient glioblastoma samples and observed high expression of CHRM3, encoding the M3 mAChR, in OPC-like cells of the proneural subtype of glioma. Studies in mouse OPC-like GSCs confirmed high levels of CHRM3 expression and demonstrated that ACh generated voltage changes and rapid (< 1 second) increases in cytosolic calcium from internal calcium stores. Exposure to a brain permeant FDA-approved anti-muscarinic drug targeting M3mAChR suppressed proliferation, evoked calcium release, and the activation of intracellular second messengers PKC and ERK. Pharmacologic inhibition of mAChRs in established patient derived glioma grafts prevented re-initiation of tumors in subsequent host animals compared with vehicle treated tumors. These studies suggest that the cholinergic microenvironment maintains GSCs in a manner similar to normal OPCs and provides a platform for repositioning available small molecule mAChR antagonists for treatment of glioma. Citation Format: Sumyuktha V. Anand, Min K. Lee, Alexander G. Skorput, Isabella B. Fox, Alison L. Young, Brock C. Christensen, Allan Gulledge, Matthew C. Havrda. Inhibition of muscarinic acetylcholine receptors in glioma stem cells blocks tumor progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5801.

Abstract 548: The microRNA-10b targeted therapeutic, TTX-MC138, is effective in preclinical pancreatic adenocarcinoma

Abstract Non-coding RNAs, such as miRNAs, represent promising targets for cancer therapy, given their role as critical players in oncogenic processes, including tumor initiation and progression, metastasis and therapeutic resistance. We and others demonstrated that miRNA-10b is a critical driver of tumor cell viability, especially in the metastatic setting. Based on this discovery, it became feasible to treat established metastatic cancer by inhibiting miR-10b. This was accomplished using a therapeutic, termed TTX-MC138, composed of antagomirs against miR-10b, conjugated to dextran-coated iron oxide nanoparticles. In our previous studies in murine models of metastatic breast cancer, we demonstrated the effectiveness of TTX-MC138 at preventing and eliminating existing metastases. Here, we describe the application of TTX-MC138 for the treatment of pancreatic adenocarcinoma. TTX-MC138 was administered weekly via intravenous injection into mice bearing orthotopic xenografts derived from human pancreatic adenocarcinoma cells. Tumor burden was measured by in vivo bioluminescence imaging. Animal survival, body weight, and tumor and metastatic burden at necropsy were also analyzed. Serum and tumor miR-10b expression, as well as global gene expression using RNA-seq were assessed to provide insight into target engagement and molecular function. Animals treated with vehicle or gemcitabine served as controls. Tumor growth rate was found to be significantly lower in animals treated with TTX-MC138 vs controls (p < 0.0001 for TTX-MC138 vs. PBS and vs. gemcitabine). Importantly, 40% of the animals treated with TTX-MC138 regressed their tumors completely as measured by bioluminescence imaging. Treatment continued for 10 weeks, after which the responding mice were monitored for disease recurrence without treatment for an additional 10 weeks. The animals showed evidence of continued weight gain and durable survival. They were sacrificed 10 weeks after treatment was discontinued, despite no evidence of morbidity, to perform necropsy. No tumors or metastases were found at the time of sacrifice. Gene expression analysis confirmed target engagement and molecular mechanism of action. Against the background of our earlier work, these studies provide further evidence of the potential of TTX-MC138 for cancer therapy and expand its relevance beyond metastatic breast cancer to also include pancreatic adenocarcinoma. Citation Format: Subrata Ghosh, Douglas Lazarus, Neil Robertson, Edward Crosier, Peter Liu, Zdravka Medarova. The microRNA-10b targeted therapeutic, TTX-MC138, is effective in preclinical pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 548.

Abstract 5655: preclinical development of a novel anti-tslpr bispecific antibody 1b7/cd3 targeting crlf2-rearranged ph-like b-all

Abstract Acute lymphocytic leukemia (ALL) is the most common form of leukemia in childhood and adolescence. Outcomes of relapsed/refractory adult B-ALL remain dismal with long-term survival of less than 10%. Although targeted therapies such as blinatumomab, inotuzumab ozogamicin, and CD19 CAR T cell therapy are a significant treatment advance for patients with B-ALL, there is still an unmet medical need for novel therapies for B-ALL. CRLF2-rearranged B-ALL, a subtype of Philadelphia chromosome-like B-ALL, is a high-risk disease subset with poor long-term outcomes. In an effort to identify new therapeutic targets for B-ALL, we validated by flow cytometry that patients with CRLF2-rearranged Ph-like ALL overexpress thymic stromal lymphopoietin receptor (TSLPR) at levels comparable with CD19. We subsequently generated antibodies against TSLPR from immunized H2L2 Harbor mice through single B cell cloning technology. The lead antibody was further engineered to a CD3-redirecting bispecific antibody (BsAb) using Xencor’s CD3e bispecific antibody technology to create 1B7/CD3 BsAb with an Fc-silent region. 1B7/CD3 BsAb exhibits high affinity binding to both human and cynomolgus monkey CD3e and TSLPR by BLI. Additionally, UHPLC-SEC analysis of 1B7/CD3 shows that this BsAb is stable without any aggregation or degradation present after five weeks incubation at 37 °C. In cell-based analyses,1B7/CD3 BsAb demonstrate potent antigen-specific T cell activation and tumor lysis activity against TSLPR+-REH and MHH-CALL4 cell lines as well as a primary B-ALL patient sample, but none against human peripheral blood mononuclear cells (PBMC) collected from healthy donors. Animal tumor models suggest that 1B7/CD3 triggers a dose-dependent tumor regression or growth inhibition in PBMC humanized TSLPR-REH CDX and BOS-1 PDX models across donors. Correspondingly, T cell activation and expansion were examined by CD69 and CD3+ T cells with the best effect observed at the 1mg/kg dose. 1B7/CD3 exhibits durable PK with T1/2 in NSG mice of up to ten days. Finally, 1B7/CD3 BsAb demonstrated a tolerable safety margin in a two-dose exploratory toxicity study in cynomolgus monkeys with MTD equal to or less than 1mg/kg. Consistent with clinical observation, we observed a transient increase of six major cytokines (IFNγ, IL-6, IL-8, IL-10, MCP-1 and TNFα) 4hr post the initial dosing, but no notable induction of cytokine levels after the second dosing (except for IL-8). Thus, our preclinical data provide the framework for the clinical evaluation of 1B7/CD3 BsAb in patients with CRLF2-rearranged B-ALL. Citation Format: Ze Tian, chunhua shi, Amin AI-Shami, GuoJun Yong, Jason K Allen, Jill Wardell Olson, Melinda G Smith, Qing Chang, Qing Shi, Junping You, Michelle A Gonzalez, Timothy E Lofton, Jasbir Kaur, Qi Zhang, DongXing Zha, Nitin Jain, Marina Y Konopleva, Timothy Heffernan, Jeffrey J Molldrem. preclinical development of a novel anti-tslpr bispecific antibody 1b7/cd3 targeting crlf2-rearranged ph-like b-all. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5655.

Abstract 4436: A novel antibody-enabled dual precision targeted protein stabilization (TPS2) that augments anti-tumor immune response by targeting CBL-B inhibitor to exhausted T cells while blocking checkpoint molecule, PD-1

Abstract It is well-established that T cells play a key role in the success of cancer immunotherapies. The goals of T cell-targeting therapies have been to restore the effector function of tumor-specific T cells that are either dysfunctional due to the immunosuppressive mechanisms in the tumor microenvironment, the lack of co-stimulatory signals, or negative regulation by expression of checkpoint molecules such as PD-1. E3 ligase Casitas B-Lineage Lymphoma Proto-Oncogene B (CBL-B) has recently gained attention as a master regulator of multiple immune-activation mechanisms. Inhibition of CBL-B enables the activation of antigen-specific T cells, and has been shown in syngeneic mouse tumor models to be efficacious as a cancer immunotherapy agent. CBL-B inhibition has also been shown to enhance and prolong the effects of anti-PD-1 antibody (Ab) therapy. However, genetic knockout of CBL-B in mice led to spontaneous autoimmunity characterized by auto-antibody production and infiltration of activated T cells and B cells into multiple organs that could result in tissue damage. In order to mitigate safety issues that could result from systemic CBL-B inhibition, we developed novel antibody-drug conjugates (ADCs) that target CBL-B inhibitors (CBL-Bi) to T cells via binding to PD-1. Using PD-1-expressing Jurkat NFAT reporter cells and mixed lymphocyte reaction assay, we demonstrated that our TPS2 approach enhanced the activation of T cells in vitro compared to treatment with anti-PD-1 Ab alone. Evaluation of pathways downstream of TCR activation in primary exhausted T cells showed increased Notch1, phospho-PLCγ2, and ZAP-70 accumulation following anti-PD-1/CBL-Bi treatment and is correlated with IFNγ induction. When autologous mature dendritic cells were co-cultured with dissociated tumor cells from melanoma patients, the highest magnitude of tumor-infiltrating lymphocyte activation was observed using delivery of CBL-Bi by anti-PD-1 ADC, compared to CBL-Bi alone, anti-PD-1 Ab alone, or combination treatment. The potential of anti-PD-1/CBL-Bi ADC for activation effector T cell function is also evident by increased intratumoral transcript levels of Granzyme B and Perforin following treatment in a humanized mouse model. In conclusion, we validated that the biological activity of CBL-Bi is retained after conjugation with an anti-PD-1 antibody. The use of anti-PD-1 Ab for developing the ADC not only targets the CBL-Bi payload to exhausted T cells but also blocks negative regulation of T cells via PD-1. Together, anti-PD-1/CBL-Bi ADC enhanced T cell activation in vitro as well as in vivo. Evaluation of safety and efficacy in animal tumor models is ongoing, to support further development of the TPS2 approach. Citation Format: Joanne Lim, Anna Skaletskaya, Uttapol Permpoon, Yeonjoon Kim, Shikha Saini, Khuloud Takrouri, Zinaida Ribkovskaia, Palash Bhar, Nathan Fishkin, Dong-Ki Choi, Ji Hyun Park, James Palacino, Peter U. Park. A novel antibody-enabled dual precision targeted protein stabilization (TPS2) that augments anti-tumor immune response by targeting CBL-B inhibitor to exhausted T cells while blocking checkpoint molecule, PD-1. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4436.

Prospects for Infrared Luminescent Diagnostics of Superficially

In this paper, we developed a promising technique for luminescent infrared (IR) diagnostics of neoplasms of visually and endoscopically accessible localization (dermatology, gynecology, dentistry) using ytterbium complexes of porphyrins. Possible mechanisms of accumulation of a pharmaceutical composition based on the ytterbium complex of 2,4-di(α-methoxyethyl)deuteroporphyrin IX (Yb-DMDP) in tumor tissues were studied. Studies on the pharmacokinetics and biodistribution of this substance in various organs and neoplasms of laboratory animals showed a significant selectivity of the accumulation of nanoparticles with ytterbium ions in tumors as early as 24 h after intravenous administration. For the purposes of luminescent IR diagnostics, a highly sensitive laser-fiber fluorimeter operating in the spectral range of 900–1100 nm was developed. Preclinical tests of the developed method of fluorescent IR cancer diagnostics were carried out and its prospects were shown.

Trichinella spiralis as a Potential Antitumor Agent: An Update

Due to the limited success of therapeutic strategies in treating tumors, a new practical potent approach is needed. This review aimed to investigate previous literature related to tumors and Trichinella spiralis (T. spiralis). In recent years, there has been growing interest in utilizing biological, viral, bacterial, yeast, and parasitic agents to cure cancers. According to several studies, some parasites could interferee with the tumors’ growth. There has been much discussion about some parasites’ applications to cure tumors in animals and humans. In studies, T. spiralis was found to have antitumor properties. The active proteins in T. spiralis, such as Caveolin-1, Heat shock proteins, and Ribosomal proteins, are thought to inhibit the growth of cancers, such as melanoma, myeloma, sarcoma, leukemia, stomach cancer, colon cancer, breast cancer, and lung cancer. In addition, these proteins are thought to induce apoptosis in specific neoplastic cells. Accordingly, antigens derived from parasites may be helpful in cancer immunotherapy. However, there are still many unanswered questions regarding Trichinella spiralis’ potential use as a biotherapy agent against cancer. Future studies should focus on the purification of parasite antigens and their use for wider-scale trials in animal models.

The presence of stem cells in ovarian cancer: a review

Ovarian cancer is one of the deadly gynecological malignancies. The disease has usually difficult to detect at the early stage as there are only a few specific symptoms and not many screening methods, thus patients usually come in an advanced and metastatic stage of the disease. Initial therapy for the disease includes surgery to remove the tumor, then followed by chemotherapy. This therapy shows a promising result at first until some sign of reoccurrence starts to show. One of the main reasons is thought to be the presence of a small subset of cells called cancer stem cells (CSCs). These cells may escape from the initial therapy, and due to the CSCs' ability to self-renew, grow into various lineages, and multiply widely. There are multiple efforts done to isolate and identify this subset cell, such as identifying the specific antigen in the cell surface, using Side Population, the ability of CSCs to form floating spheres in serum-free media, and the level of ALDH expression. Such methods have been performed together to identify purely cancer stem cells from the malignancy. The ability of the cell to produce new tumors in immuno-deficient animals, however, is the gold standard for identifying CSC, according to the current study. This review will discuss several methods that have been used to isolate cancer stem cells and prove the stemness of these cells by injecting them into immuno-deficient mice. Cancer stem cells also can avoid the effect of chemotherapy. Several things contribute to this ability. This review there will discuss methods that have been several things that make it possible to be able to escape chemotherapy drugs. By understanding these mechanisms, hopefully, new therapy modalities will be developed and specifically targeted, so that can be used to treat malignancies more effectively.

Oncogenic Viruses-Encoded microRNAs and Their Role in the Progression of Cancer: Emerging Targets for Antiviral and Anticancer Therapies.

Approximately 20% of all cases of human cancer are caused by viral infections. Although a great number of viruses are capable of causing a wide range of tumors in animals, only seven of these viruses have been linked to human malignancies and are presently classified as oncogenic viruses. These include the Epstein-Barr virus (EBV), human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), Merkel cell polyomavirus (MCPyV), human herpesvirus 8 (HHV8), and human T-cell lymphotropic virus type 1 (HTLV-1). Some other viruses, such as the human immunodeficiency virus (HIV), are associated with highly oncogenic activities. It is possible that virally encoded microRNAs (miRNAs), which are ideal non-immunogenic tools for viruses, play a significant role in carcinogenic processes. Both virus-derived microRNAs (v-miRNAs) and host-derived microRNAs (host miRNAs) can influence the expression of various host-derived and virus-derived genes. The current literature review begins with an explanation of how viral infections might exert their oncogenic properties in human neoplasms, and then goes on to discuss the impact of diverse viral infections on the advancement of several types of malignancies via the expression of v-miRNAs. Finally, the role of new anti-oncoviral therapies that could target these neoplasms is discussed.

Evaluation of the in vitro and in vivo effect of liposomal doxorubicin along with oncolytic Newcastle disease virus on 4T1 cell line: Animal preclinical research.

Breast cancer is one of the most common malignancies in women, with one in 20 globally. Oncolytic viruses have recently been the first step in the biological treatment of cancer, either genetically engineered or naturally occurring. They increase specifically inside cancer cells and destroy them without damaging normal tissues or producing a host immune response against tumour cells or expressing transgenes. One of the most known members of this family is the Newcastle disease virus (NDV), a natural oncolytic virus that selectively induces apoptosis and DNA fragmentation in human cancer cells. This study performed biochemical and molecular investigations with variable doses of NDV (32, 64, 128 HAU) and liposomal doxorubicin (9mg/kg) on mouse triple-negative mammary carcinoma cell line 4T1 and BALB/c models tumours for the first time. Real-time quantitative PCR analysis in NDV-treated animal tumours showed increased expression of P21, P27 and P53 genes and decreased expression of CD34, integrin Alpha 5, VEGF and VEGF-R genes. Additional assessments in treated mouse models also showed that NDV increased ROS production, induced apoptosis, reduced tumour size and significantly improved prognosis, with no adverse effect on normal tissues. These findings all together might indicate that NDV in combination with chemotherapy drugs could improve prognosis in cancer patients although many more conditions should be considered.

An Experimental Study: Treatment of Subcutaneous C6 Glioma in Rats Using Acoustic Droplet Vaporization.

The objective of this study was to investigate the treatment effects of acoustic droplet vaporization (ADV) on tumors. Experiments were conducted on subcutaneous C6 glioma implanted in 37 rats. Twenty-five rats were divided into five groups treated by ultrasound (US) + dodecafluoropentane (DDFP), US + microbubble (MB), US, DDFP, or saline, respectively. ADV was performed using DDFP droplets (2-5μm) triggered by non-focused pulsed ultrasound. Macroscopic and histological changes of the tumor were compared with investigation of the tumor ablation effect of ADV. Tumor temperature was measured before and immediately after treatment to explore temperature changes. Furthermore, another 12 rats with bilateral tumors were divided into two groups. Six animals received ADV treatment on unilateral tumor, while another six received saline injection on unilateral tumor. The tumor blood perfusion, tumor volume and related immune response were measured. The tumors treated by ADV were partially damaged without significant temperature rise. For the animals with bilateral tumors, the tumor blood perfusion around the damaged area on the side receiving ADV still existed. Additionally, the bilateral tumors of animals treated with ADV were smaller than those of animals treated with saline, along with stronger immune response and more tumor cell apoptosis in tumors on both sides. The study demonstrated that ADV treatment could damage subcutaneous glioma in rats by mechanical effect and enhance systemic immune response to furtherly inhibit the tumor growth.

The role of mitochondria in the development of breast cancer

There is a hypothesis that mitochondrial dysfunction and mutations in the mitochondrial genome may play an important role in the carcinogenesis; however, despite many years of research, this issue is still the subject of scientific discussion. The review reflects modern views on the role of mitochondria and the mitochondrial genome in the development of breast cancer. Sources were searched in Pubmed and eLIBRARY.RU databases for the past 10 years and in article references. Articles were selected that contained data from case-control studies of breast cancer and studies of cybrid cells.
 The survey of experimental and association studies has shown that the mitochondrial genome determines the characteristics of cellular metabolism in human populations at the global (by macrohaplogroups L, M, N), landscape (by haplogroups), population (by subhaplogroups), and individual levels (by SNPs, insertions, deletions) and can determine predisposition to cancer. Single nucleotide substitutions, deletions, and mitochondrial DNA copy number decline are not specific for breast cancer. Nevertheless, mitochondria have been experimentally shown to be directly involved in the development of malignant neoplasms in experimental animals. It is likely that mitochondrial involvement in carcinogenesis is associated with mitochondrial dysfunction, in which nuclear-mitochondrial relationships are disrupted. On the other hand, mutations with too strong effect, i.e., completely disrupting mitochondrial function, lose their tumorigenic potential. Mutations, deletions and changes in mitochondrial DNA copy number are undoubtedly associated with the development of breast cancer, being one of the most important elements of a complex web of numerous interactions.

Assessing the effects of ultrasound parameters on P-selectin expression for active targeting of nanotherapeutics

P-selectin is a nanotherapeutic target for enhanced passage of nanoscale drug delivery systems across the vascular barrier and into tumors via transcytosis. While many tumors express P-selection, radiation can be used to induce expression in tumors devoid of P-selectin. This study aims to test whether ultrasound can elicit a similar response through mechanical or thermal bioeffects. Preliminary experiments were performed in vitro using brain tissue derived mouse endothelial cells. A Vevo SoniGene system was used to sonicate cells with low-intensity (2 W/cm2) pulsed ultrasound in a 12-well cell culture plate. Upregulation of P-selectin was seen using a 60 second treatment duration at 50% and 100% duty cycles via flow cytometry analysis. The mean fluorescence intensity, normalized to nontreated cells, was 32 + /- 17.4 and 103 + /- 37.2 for 50% and 100% duty cycles, respectively. Viability remained high with 72.6 + /- 14.5 and 77.5 + /- 8.3% of cells viable for both 50% and 100% duty cycle groups, respectively. These results highlight the potential of ultrasound for active targeting using non-ionizing energy and for tumors where radiation is not feasible. Future studies will identify associated bioeffects and compare ultrasound with radiation for nanotherapeutic delivery in small animal tumor models.

Potent bromodomain and extraterminal domain inhibitor JAB-8263 suppresses MYC expression and exerts anti-tumor activity in colorectal cancer models.

The overexpression of the MYC gene plays an important role in the occurrence, development and evolution of colorectal cancer (CRC). Bromodomain and extraterminal domain (BET) inhibitors can decrease the function BET by recognizing acetylated lysine residues, thereby downregulating the expression of MYC. To investigate the inhibitory effect and mechanism of a BET inhibitor on CRC cells. The effect of the BET inhibitor JAB-8263 on the proliferation of various CRC cell lines was studied by CellTiter-Glo method and colony formation assay. The effect of JAB-8263 on the cell cycle and apoptosis of CRC cells was studied by propidium iodide staining and Annexin V/propidium iodide flow assay, respectively. The effect of JAB-8263 on the expression of c-MYC, p21 and p16 in CRC cells was detected by western blotting assay. The anti-tumor effect of JAB-8263 on CRC cells in vivo and evaluation of the safety of the compound was predicted by constructing a CRC cell animal tumor model. JAB-8263 dose-dependently suppressed CRC cell proliferation and colony formation in vitro. The MYC signaling pathway was dose-dependently inhibited by JAB-8263 in human CRC cell lines. JAB-8263 dose-dependently induced cell cycle arrest and apoptosis in the MC38 cell line. SW837 xenograft model was treated with JAB-8263 (0.3 mg/kg for 29 d), and the average tumor volume was significantly decreased compared to the vehicle control group (P < 0.001). The MC38 syngeneic murine model was treated with JAB-8263 (0.2 mg/kg for 29 d), and the average tumor volume was significantly decreased compared to the vehicle control group (P = 0.003). BET could be a potential effective drug target for suppressing CRC growth, and the BET inhibitor JAB-8263 can effectively suppress c-MYC expression and exert anti-tumor activity in CRC models.