Search

Objective: Fluorescence molecular tomography (FMT) is a promising medical imaging technology aimed at the non-invasive, specific, and sensitive detection of the distribution of fluorophore. Conventional sparsity prior-based methods of FMT commonly face problems such as over-sparseness, spatial discontinuity, and poor robustness, due to the neglect of the interrelation within the local subspace. To address this, we propose an adaptive group orthogonal matching pursuit (AGOMP) method. Methods: AGOMP is based on a novel local spatial-structured sparse regularization, which leverages local spatial interrelations as group sparsity without the hard prior of the tumor region. The adaptive grouped subspace matching pursuit method was adopted to enhance the interrelatedness of elements within a group, which alleviates the over-sparsity problem to some extent and improves the accuracy, robustness, and morphological similarity of FMT reconstruction. A series of numerical simulation experiments, based on digital mouse with both one and several tumors, were conducted, as well as in vivo mouse experiments. Results: The results demonstrated that the proposed AGOMP method achieved better location accuracy, fluorescent yield reconstruction, relative sparsity, and morphology than state-of-the-art methods under complex conditions for levels of Gaussian noise ranging from 5–25%. Furthermore, the in vivo mouse experiments demonstrated the practical application of FMT with AGOMP. Conclusion: The proposed AGOMP can improve the accuracy and robustness for FMT reconstruction in biomedical application. [ABSTRACT FROM AUTHOR]

Liver metastasis, characterized by the spread of tumors to the liver from other areas, represents a deadly disease with poor prognosis. Currently, there is no effective therapeutic strategies and/or agents to combat liver metastasis primarily due to the insufficient understanding of liver metastasis. To develop a promising strategy for targeting liver metastasis, understanding of a cell origin responsible for liver metastasis and how this cell can be pharmacologically eliminated are therefore crucial. Using diverse tumor models including p53−/− genetic mouse model and syngeneic tumor models, we identified primordial germ cell (PGC)-like tumor cells, which are enriched in earliest liver micro-metastasis (up to 99%), as a cell origin of liver metastasis. PGC-like tumor cells formed earliest micro-metastasis in liver and gradually differentiated into non-PGC-like tumor cells to constitute late macro-metastasis in the course of tumor metastasis. The liver metastasis-initiating cells (PGC-like tumor cells) display cell renewal and differentiation capabilities, resemble primordial germ cells (PGCs) in morphology and PGC marker gene expression, and express higher level of the genes linked to metastasis and immune escape compared with non-PGC-like tumor cells. Of note, Stellarhigh PGC-like tumor cells, but not Stellarlow non-PGC-like cells, sorted from primary tumors of p53−/− mice readily form liver metastasis. Depletion of PGC-like tumor cells through genetic depletion of any of key germ cell genes impairs liver metastasis, while increased PGC-like tumor cells by SMAD2 knockout is correlated with markedly enhanced liver metastasis. Finally, we present the proof of principle evidence that pharmacologically targeting BMP pathways serves as a promising strategy to eliminate PGC-like tumor cells leading to abrogating liver metastasis. Collectively, our study identifies PGC-like tumor cells as a cell origin of liver metastasis, whose depletion by genetically targeting core PGC developmental genes or pharmacologically inhibiting BMP pathways serves a promising strategy for targeting liver metastasis. [ABSTRACT FROM AUTHOR]

Tumour hypoxia is a well‐established factor of resistance in radiation therapy (RT). Myo‐inositol trispyrophosphate (ITPP) is an allosteric effector that reduces the oxygen‐binding affinity of haemoglobin and facilitates the release of oxygen by red blood cells. We investigated herein the oxygenation effect of ITPP in six tumour models and its radiosensitizing effect in two of these models. The evolution of tumour pO2 upon ITPP administration was monitored on six models using 1.2 GHz Electron Paramagnetic Resonance (EPR) oximetry. The effect of ITPP on tumour perfusion was assessed by Hoechst staining and the oxygen consumption rate (OCR) in vitro was measured using 9.5 GHz EPR. The therapeutic effect of ITPP with and without RT was evaluated on rhabdomyosarcoma and 9L‐glioma rat models. ITPP enhanced tumour oxygenation in six models. The administration of 2 g/kg ITPP once daily for 2 days led to a tumour reoxygenation for at least 4 days. ITPP reduced the OCR in six cell lines but had no effect on tumour perfusion when tested on 9L‐gliomas. ITPP plus RT did not improve the outcome in rhabdomyosarcomas. In 9L‐gliomas, some of tumours receiving the combined treatment were cured while other tumours did not benefit from the treatment. ITPP increased oxygenation in six tumour models. A decrease in OCR could contribute to the decrease in tumour hypoxia. The association of RT with ITPP was beneficial for a few 9L‐gliomas but was absent in the rhabdomyosarcomas. [ABSTRACT FROM AUTHOR]

This article presents the historical control data of spontaneous tumors in Tg.rasH2 published in 2013 (2004–2012) and compares and contrasts it to more recent data collected from 2013 to 2018, reporting differences in the average percentage incidences or incidence ranges as well as the incidence of new tumors. In 2013, we published a comprehensive review of spontaneous tumors in Tg.rasH2 mice used in 26-week carcinogenicity studies, which included data from control dose groups from 26 studies and a total of 710 mice per sex. The total database, now including the more recent data, has nearly doubled the number of animals, completing to date a total of 52 studies in males and 51 studies in females for a total of 1,615 male mice and 1,560 female mice, respectively. In this article, we compare the data collected from 2004 to 2012 against the data collected from 2013 to 2018 and the overall tumor incidence change. [ABSTRACT FROM AUTHOR]

A 24-month oral carcinogenicity study of permethrin was conducted by feeding male and female CD-1 mice diets containing concentrations of 0, 20, 500, and 2,000 ppm of permethrin (males) or 0, 20, 2,500, and 5,000 ppm of permethrin (females). After approximately two years on study, surviving mice were sacrificed for the evaluation of chronic toxicity and/or carcinogenicity. An expert panel of pathologists was convened as a Pathology Working Group (PWG) to review coded liver histology sections from male and female mice and to classify all liver neoplasms according to current nomenclature and diagnostic criteria guidelines. The PWG results indicate that permethrin induced a significant dose-dependent increase in the incidence of hepatocellular neoplasms in treated female mice (p < .01) as well as a nonstatistically significant increase in the incidence of hepatocellular tumors in treated male mice. Given the continuum of the diagnoses of adenoma and carcinoma, and the difficulty in distinguishing some of the lesions, it is appropriate to consider only the combined incidences of hepatocellular tumors (adenoma and/or carcinoma) for biological significance and risk assessment. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is a common malignant disease that is prevalent in Asian countries. Atypical chemokine receptor 4 (ACKR4) binds to various chemokines, including C-C motif chemokine ligand (CCL)19, CCL21, CCL25 and C-X-C motif chemokine ligand 13, without inducing downstream signaling transduction. However, the role of ACKR4 in modulating NPC development remains unclear. In the present study, the effects of ACKR4 on NPC growth, invasion and metastasis were investigated, as well as the endogenous mechanisms through which ACKR4 mediates NPC development. The results demonstrated that ACKR4 was downregulated in human NPC tumor tissues, as compared with that in adjacent normal tissue. In a subcutaneous tumor animal model, the knockdown of ACKR4 enhanced NPC invasion and metastasis. Furthermore, CCL21 was accumulated in ACKR4 knockdown tumors. In vitro, the loss of ACKR4 increased CCL21-mediated SUNE-1 cell proliferation, epithelial-mesenchymal transition and invasion. In conclusion, the loss of ACKR4 promoted CCL21-mediated NPC development; thus, neutralizing CCL21 in NPC with low ACKR4 expression may be a novel treatment strategy. [ABSTRACT FROM AUTHOR]

One approach to improve the targeted therapeutic efficiency of lung cancer is to deliver drugs using nano-scaled systems. In this study, RGD peptide-modified, paclitaxel (PTX) prodrug-based, dual-drugs loaded, and redox-sensitive lipid-polymer nanoparticles were developed and the in vitro and in vivo antitumor efficiency was evaluated in lung cancer cells and tumor bearing animal models. RGD-modified PTX and cisplatin (CDDP) loaded LPNs (RGD-ss-PTX/CDDP LPNs) have sizes around 190 nm, and zeta potentials of −35 mV. The half-maximal inhibitory concentration (IC50) values were 26.7 and 75.3 μg/mL for drugs loaded LPNs and free drugs combination, which indicates significantly higher antitumor activity of LPNs than free drugs. RGD-ss-PTX/CDDP LPNs also exhibited the best antitumor efficiency in vivo , which inhibited the tumor size of mice from 1486 mm 3 to 263 mm 3 . The results illustrated that the system could successfully load drugs and achieve synergistic combination lung cancer treatment efficiency with lower systemic toxicity compared with free drugs counterparts. The resulting system could be facilitated as a promising targeted nanomedicine for the treatment of lung cancer. [ABSTRACT FROM AUTHOR]

PET images deliver functional data, whereas MRI images provide anatomical information. Merging the complementary information from these two modalities is helpful in oncology. Alignment of PET/MRI images requires the use of multi-modal registration methods. Most of existing PET/MRI registration methods have been developed for humans and few works have been performed for small animal images. We proposed an automatic tool allowing PET/MRI registration for pre-clinical study based on a two-level hierarchical approach. First, we applied a non-linear intensity transformation to the PET volume to enhance. The global deformation is modeled by an affine transformation initialized by a principal component analysis. A free-form deformation based on B-splines is then used to describe local deformations. Normalized mutual information is used as voxel-based similarity measure. To validate our method, CT images acquired simultaneously with the PET on tumor-bearing mice were used. Results showed that the proposed algorithm outperformed affine and deformable registration techniques without PET intensity transformation with an average error of 0.72 ± 0.44 mm. The optimization time was reduced by 23% due to the introduction of robust initialization. In this paper, an automatic deformable PET-MRI registration algorithm for small animals is detailed and validated. Graphical abstract ᅟ. [ABSTRACT FROM AUTHOR]

Background: Fine‐needle aspiration cytology (FNAC) of lymph nodes (LNs) is routinely used for staging canine malignant solid tumors, but studies evaluating its efficacy are limited. Objectives: The primary objectives of this study were to evaluate the sensitivity/specificity of FNAC and the significance of nondiagnostic FNAC when staging canine malignant tumors. A secondary objective was to determine the prevalence of multiple nodal metastases. Methods: Lymph nodes draining malignant solid tumors assessed with FNAC and histopathology were included. The sensitivity/specificity of FNAC was determined for LNs with diagnostic FNAC, using histopathology as the gold standard. The proportion of nondiagnostic FNAC and associated histopathologic prevalence of metastasis were determined. Among the tumors with multiple LNs assessed, the prevalence of multiple nodal metastases was determined. Results: The sensitivity of FNAC (194 LNs) was 67% for sarcomas, 100% for carcinomas, 63% for melanomas, 75% for mast cell tumors, and 100% for other round cell tumors. The specificity varied between 83% and 96%. Nondiagnostic FNAC was reported in 25% of LNs sampled (65/259), most of which were nonenlarged and/or difficult to access, and 20% of which were metastatic on histopathology. When several LNs were assessed (88/189 tumors), the prevalence of multiple nodal metastases was 24%. Conclusions: Histopathologic LN evaluation cannot be robustly substituted with FNAC when staging selected canine solid tumors. When a diagnostic FNAC is elusive, the histopathologic assessment remains ideal. Finally, staging should not always be limited to the assessment of a single LN. [ABSTRACT FROM AUTHOR]

Animal models for examining human breast cancer (HBC) carcinogenesis have been extensively studied and proposed. With the recent advent of immunotherapy, significant attention has been focused on the dog as a model for human cancer. Dogs develop mammary tumors and other cancer types spontaneously with an intact immune system, which exhibit a number of clinical and molecular similarities to HBC. In addition to the spontaneous tumor presentation, the clinical similarities between human and canine mammary tumors (CMT) include the age at onset, hormonal etiology and course of the diseases. Furthermore, factors that affect the disease outcome, including tumor size, stage and lymph node invasion, are similar in HBC and CMT. Similarly, the molecular characteristics of steroid receptor, epidermal growth factor, proliferation marker, metalloproteinase and cyclooxygenase expression, and the mutation of the p53 tumor suppressor gene in CMT, mimic HBC. Furthermore, ductal carcinomas in situ in human and canine mammary glands are particularly similar in their pathological, molecular and visual characteristics. These CMT characteristics and their similarities to HBC indicate that the dog could be an excellent model for the study of human disease. These similarities are discussed in detail in the present review, and are compared with the in vitro and other in vivo animal models available. [ABSTRACT FROM AUTHOR]

Incidence of testicular germ cell tumors (TGCT) has been continuously rising (1-5% per year), (1). In Croatia the incidence of TGCT is increasing at the highest rate in the world. Croatia also has a high rate of mortality compared to other countries (2). Germ cell neoplasia in situ (GCNIS) is a precursor lesion of TGCT's which makes up to 95% of all testicular tumors. TGCT are divided into pure seminomatous tumors and mixed germ cell tumors (non-seminomas). GCNIS is considered to be driven by an interplay of genetic, epigenetic and micro-environmental factors that lead up to an arrest of gonocyte differentiation (3,4). GCNIS is reprogrammed in the development of non-seminomas into embryonal carcinoma (EC) cells, which make up the pluripotent core of the nonseminomas (3). EC cells are highly similar to embryonic stem cells, expressing the same pluripotency markers OCT4, SOX2 and NANOG. EC cells differentiate into teratoma tissue, or retain their pluripotency and high malignancy as in teratocarcinoma (5). The well-known and established experimental mouse model for teratocarcinoma, at the Biology Department of Zagreb's School of Medicine, has been described based on histological/histochemical methods and its molecular signature has not yet been studied (6). The aim of this study was to compare the rate of apoptotic activity in the experimental mouse model as well as in human teratocarcinomas. Caspase-3 is the most important apoptotic executioner caspase in apoptosis and is activated by both intrinsic and extrinsic pathways. Some authors consider that Caspase-3 plays a critical role in ES cell differentiation by negatively regulating the self-renewal machinery of these stem cells, in part by cleaving Nanog (7,8). Formalin-fixed paraffin-embedded tissue from 10 testicular teratocarcinoma from the Ljudevit Jurak Pathology and Cytology Department Archive and 10 animal model tumors from the Biology Department of Zagreb's School of Medicine were used for immunohistochemical detection of Caspase-3. Slides were analyzed semi-quantitatively, at the area of strongest reaction, by two pathologist (S.M. and M.U.), on a scale from 0-3, depending on the percentage of reactive cells. The data were analyzed in GraphPad Prism using the Mann-Whitney test. The results have shown a statistically significant difference in the rate of apoptosis between the human teratocarcinomas and the experimental mouse model, with the mouse model showing a higher rate (more than 25% of positive cells) in 64% of tumors compared to 30% of human tumors with highest reaction. The difference could be in part attributed to the fact that the study was a pilot with a relatively small sample pool, and the difference in biological development and "age" between the human and mouse model teratocarcinomas which was obtained uniformly. Western Blot analysis of Caspase-3 activity should be done to verify the results and a bigger cohort should be studied (Figure 1). [ABSTRACT FROM AUTHOR]

ABSTRACT: New treatment options are urgently required in the field of chondrosarcoma, particularly of chondrosarcomas with a well‐differentiated hyaline cartilage‐like extracellular matrix (e.g., collagen II and proteoglycan‐rich) phenotype, notoriously resistant to drug penetration, and having potential of progression towards higher grade. We investigated the feasibility of using 5′‐methylschweinfurthin G (MeSG) as a tumor suppressor agent in the Swarm rat chondrosarcoma, an intermediate‐ to high‐grade chondrosarcoma model, having a hyaline cartilage‐like phenotype. Tumor cell culture studies were performed to identify their proliferative and cytotoxicity sensitivity to MeSG. Tumor burden mice were treated with MeSG and analyzed for tumor growth, morphology and regression. The chondrosarcoma tumor cells had a half maximum cytotoxicity concentration (IC50) of 35 nM MeSG; approximately 300‐fold less than freshly isolated rat chondrocytes (IC50 of 11 µM). Multiple injections of MeSG (20 mg/kg, body weight) resulted in reduced/eliminated tumor growth over a 17‐day period in mice, and an 83% reduction (p = 0.023) in tumor mass. Three out of ten MeSG treated mice had complete elimination of tumor. Tumors of treated mice had a decrease in chondrosarcoma cell proliferation (p = 0.012) and an increase in cell death (p = 0.030) compared with tumors of control mice. These findings in an animal model demonstrate the effectiveness of MeSG for treatment of rat chondrosarcomas, and may have the potential use as a therapeutic option for the difficult‐to‐treat intermediate‐to high‐grade hyaline cartilage‐like chondrosarcoma. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1283–1293, 2018. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is one of the most malignant cancers. MicroRNAs (miRs) were reported to play important roles in GBM recently. However, the role of a novel miR-186-5p in GBM tumorigenesis is still elusive. Using bioinformatics, miR-186-5p was identified as potential regulators of both fibroblast growth factor (FGF)-2 and NF-κB subunit RelA. Luciferase reporter assay was used to confirm the direct recognition FGF2 and RelA mRNAs by miR-186-5p. Invasion and migration assays were employed to study the effect of miR-186-5p on GBM cell growth in vitro. Xenograft tumor animal model was established to elucidate the in vivo function of miR-186-5p. MiR-186-5p directly targeted mRNAs of both FGF2 and RelA, and repressed their expressions. Invasive and migratory abilities of GBM cells and growth of xenograft tumors were significantly inhibited by miR-186-5p, which can be restored by re-introduction of FGF2 and RelA expressions. MiR-186-5p is a novel tumor suppressor miR that functions to inhibit tumorigenesis of GBM both in vitro and in vivo, by targeting both FGF2 and RelA. MiR-186-5p/FGF2/RelA pathway may be potentially used as molecular targets of in the clinical treatment of GBM. [ABSTRACT FROM AUTHOR]

Background Higher rates of local recurrences and second primaries, ascribable to field cancerization, are known problem in oral cancers. The present study explored utility of identification of potential recurrences by Raman spectroscopy, which has been shown to identify oral precancers, cancers, and field cancerization in humans and micro-sized mechanical irritation-induced tumors in animals. Methods Raman spectra were acquired from tumor and contralateral normal mucosa in 99 patients with oral cancer who were then followed up for appearance of clinically apparent cancerous lesions. Misclassifications observed in subsequent multivariate statistical analysis between contralateral normal and tumor spectra were correlated with appearance of new malignant lesions. Results The patients with mismatched spectra had 1.5 times higher chances of developing local recurrence. The sensitivity of Raman spectroscopy in predicting the recurrences was 80% and the specificity was 29.7%. Conclusion Findings provide proof-of-concept for Raman spectroscopy-based identification of sites that have higher propensity to progress to carcinomas before becoming clinically apparent. Prospective validation of Raman spectroscopy by including additional oral cavity subsites and use of multifiber bundles may improve rate of identification of recurrence-prone subjects. [ABSTRACT FROM AUTHOR]

The present study evaluated the in vivo antitumor effects and toxicity of a new Ru(II) compound, cis-(Ru[phen] 2 [ImH] 2 ) 2+ (also called RuphenImH [RuC]), against Walker-256 carcinosarcoma in rats. After subcutaneous inoculation of Walker-256 cells in the right pelvic limb, male Wistar rats received 5 or 10 mg kg −1 RuC orally or intraperitoneally (i.p.) every 3 days for 13 days. A positive control group (2 mg kg −1 cisplatin) and negative control group (vehicle) were also used. Tumor progression was checked daily. After treatment, tumor weight, plasma biochemistry, hematology, oxidative stress, histology, and tumor cell respiration were evaluated. RuC was effective against tumors when administered i.p. but not orally. The highest i.p. dose of RuC (10 mg kg −1 ) significantly reduced tumor volume and weight, induced oxidative stress in tumor tissue, reduced the respiration of tumor cells, and induced necrosis but did not induce apoptosis in the tumor. No clinical signs of toxicity or death were observed in tumor-bearing or healthy rats that were treated with RuC. These results suggest that RuC has antitumor activity through the modulation of oxidative stress and impairment of oxidative phosphorylation, thus promoting Walker-256 cell death without causing systemic toxicity. These effects make RuC a promising anticancer drug for clinical evaluation. [ABSTRACT FROM AUTHOR]

Diallyl trisulfide (DATS), a natural agent derived from garlic, has been tested for its antigastric cancer activities in various preliminary studies. However, more systematic pharmacodymatic (PD) and mechanistic evaluations are clearly needed. The aim of this study was to investigate the antitumor effects of DATS in the treatment of human gastric cancer cell SGC-7901 both in vitro and in vivo using widely recommended study procedures. DATS suppressed cancer cells proliferation and induced cell cycle arrest accompanied by an increase in the expressions of cyclin A2 and cyclin B1 in SGC-7901 cancer cells. DATS also caused an increase in apoptotic cell death, which involved in accumulations of bax, p53, and cytochrome C and reduction of Bcl-2 expressions. Besides, activation of JNK, ERK and p38 phosphorylation in DATS-treated cells suggested that mitogen-activated protein kinase (MAPKs) pathways were involved in DATS-induced apoptosis. Meanwhile, DATS significantly inhibited tumor growth and promoted tumor apoptosis in a xenograft model of gastric cancer cell SGC-7901. DATS inhibited tumor migration and invasion by modulating MMP9 and E-cadherin protein expressions. In addition, DATS treatment evidently increased the cytokine secretions of IL-12, TNF-α and IFN-γ (p < 0.05). Biochemical serum analysis and histopathological examination indicated no obvious side effects in major mouse organs. Therefore, our findings provide a framework for further exploration of DATS as a novel chemotherapeutic for human gastric cancer. [ABSTRACT FROM AUTHOR]

Summary Peripheral nerve sheath tumours (PNSTs) are neoplastic growths derived from Schwann cells, perineural cells or both. Malignant PNSTs (MPNSTs) are uncommon in domestic animals. This report describes the concomitant occurrence of PNSTs in a 10-year-old female cocker spaniel with a clinical history of respiratory impairment. Grossly, there was a large infiltrative mass in the caudal lobe of the right lung; smaller nodules were observed in the other lobes of the right lung. Furthermore, a small encapsulated cutaneous nodule was observed on the left hindlimb. Histopathology of the pulmonary tumours revealed the proliferation of pleomorphic spindle-shaped cells with moderate mitotic index arranged in interwoven bundles and concentric Antoni A and Antoni B patterns; invasion of the adjacent pulmonary tissue was observed. The cutaneous nodule consisted of neoplastic mesenchymal cells in interwoven bundles with concentric whorls, but without the marked anisokaryosis, binucleation and infiltrative growth seen in the pulmonary tumour. Immunohistochemistry revealed that both tumours were immunoreactive for vimentin, glial fibrillary acidic protein and S100 protein, but were negative for factor VIII. These findings are indicative of a MPNST in the lung with a concomitant benign PNST in the limb. This case represents the first report of a primary MPNST in the lung of a dog. This neoplastic growth should be included in the differential diagnosis of primary malignant pulmonary tumours of dogs. [ABSTRACT FROM AUTHOR]

Background: Cutaneous squamous cell carcinoma of the nasal planum in cats is a common indication for antitumor treatment such as external beam radiation therapy. Curative-intent radiation therapy has been described as a valuable treatment option, resulting in long and stable tumor control in these patients. The aim of the current study was to evaluate outcome and toxicity, as well as possible prognostic factors using an accelerated hypofractionated radiation therapy protocol. Cats with squamous cell carcinoma of the nasal planum treated with an accelerated radiation protocol (10 x 4.8 Gy, over one week) were retrospectively evaluated. Tumor- and treatment-associated variables were evaluated in respect to local control and survival. Results: Forty-four cats met the inclusion criteria for this study. All cats showed complete response to therapy. Median disease-free interval (DFI) for all cases was 916 days (95% CI: 456-1377). One- and two-year DFIs were 71% (95% CI: 56-86%) and 60% (95% CI: 43-77%). Of the tested variables, only tumor volume showed a tendency to influence DFI, with larger tumors having a 5.4 times greater risk of recurrence than the smaller ones (HR 1.33 (95% CI: 0.99-1.79), p = 0.054). Median overall survival (OS) was 902 days (95% CI: 862-942). One- and 2-year OSs were 79.3% (95% CI: 67.3-91.3) and 58.4% (95% CI: 42.8-74). Of the tested variables, again, only tumor volume influenced OS with larger tumors having a 6.3 times greater risk of dying than the smaller ones (HR 1.36 (95% CI: 1.07-1.73), p = 0.010). The acute and late toxicity profile was low and hence clinically acceptable. Conclusions: Curative-intent radiation therapy with an accelerated fractionation schedule can be considered a safe, cosmetically superior treatment option for cutaneous squamous cell carcinomas of the nasal planum in cats, resulting in long and stable tumor control. [ABSTRACT FROM AUTHOR]

ABSTRACT Aim Nitidine (NTD) has been reported to specifically inhibit the growth of human A549 non-small-cell lung cancer cells via selective intracellular accumulation. Our recent study showed that NTD preferentially accumulates in camptothecin-resistant A549 cells (CRC) compared with normal A549 cells (nA549) in vitro. Here, we examined the in vivo anti-tumor effects of NTD on CRC-derived tumors and oral treatment on nA549 using a xenograft mouse model. Methods Cancer cells were intradermally inoculated into the back of mice. Then, 100 µg NTD was injected i.p. into the nA549- or CRC-derived tumor-bearing mice. To confirm the anti-tumor effects of oral NTD, the nA549-transplanted mice were fed a diet containing NTD concentrate prepared from Toddalia asiatica Lam. Results The anti-tumor effect of NTD (i.p.) manifested earlier in CRC-derived tumors than in the A549-derived tumors. Oral NTD concentrate also significantly inhibited the growth of the nA549-derived tumors. NTD was detected in the tumor but not in other tissues in the NTD concentrate-fed mice. Conclusion CRC-derived tumor was more susceptible to NTD treatment than nA549-derived tumor. Furthermore, the anti-tumor effect of oral NTD and its preferential accumulation in tumor tissues have been demonstrated for the first time. This may be useful for the development of safe anti-cancer drugs. [ABSTRACT FROM AUTHOR]

In this study, non-neoplastic and neoplastic lesions in the urinary bladders of water buffalo were determined in the Marmara, the central and western part of the Black Sea region of Turkey. In this context, water buffalo with lesions in the urinary bladder were obtained from the private and public slaughterhouses of several provinces. The lesions were evaluated pathologically and immunohistochemically. In addition, species of bracken ferns were identified in these provinces. Histopathologically, 39 of the collected tissue samples were diagnosed as neoplasia. These neoplasms were classified and graded according to The World Health Organization Classification of Tumours published in 2004. In this context, papilloma (16 cases), papillary urothelial neoplasm of low malignant potential (PUNLMP) (7 cases), low-grade papillary carcinoma (13 cases), high-grade papillar carcinoma (2 cases), and low-grade papillary carcinoma with hemangiosarcoma (1 case) were detected in samples diagnosed as neoplasia. In the collected bracken ferns, Athyrium filix-foemina (L.) Roth; Dryopteris dilatata (Hoffm.) Gary; Dryopteris filix-mas (L.) Schott; Polystichum aculeatum (L.) Roth; Polystichum setiferum (Forsk.) Woynar; Polystichum woronowii Fomin, Polypodium vulgare L. and Pteridium aquilinum (L.) Kuhn spp. were identified. As a result, it has been understood that the consumption of identified bracken ferns leads more frequently to epithelial neoplasms. [ABSTRACT FROM AUTHOR]

This study aimed to determine the treatment response of canine nasal tumor treated with only linear accelerated radiation therapy ( LINAC) using volumetric measurement criteria at Kasetsart University Veterinary Teaching Hospital between May 2013 and August 2015. Medical records of the patients including age, breed, sex, histopathological diagnosis, clinical stage, types of radiation therapy and complications of treatment were recorded. All 20 dogs were irradiated with total dose ranging from 36 to 54 Gray (Gy) . Computed tomography was performed with all dogs before and three months after treatment in order to evaluate tumor volume change. Results revealed that median survival time for all dogs was 383 days (95%CI 214.69-551.31) and median progression free was 384 days (95%CI 240.94-527.06) . Considering tumor volume change, six dogs (30%) were classified as partial response at 3 months after radiation therapy, while 14 dogs (70%) were classified as stable disease. In addition, considering variables associated with survival time analyzed by log-rank test, it was found that age and volumetric measurement response correlated with survival time statistically significantly (P<0.05). [ABSTRACT FROM AUTHOR]

Probing tumor extracellular metabolites is a vitally important issue in current cancer biology. In this study an analytical system was constructed for the in vivo monitoring of mouse tumor extracellular hydrogen peroxide (H 2 O 2 ), lactate, and glucose by means of microdialysis (MD) sampling and fluorescence determination in conjunction with a smart sequential enzymatic derivatization scheme—involving a loading sequence of fluorogenic reagent/horseradish peroxidase, microdialysate, lactate oxidase, pyruvate, and glucose oxidase—for step-by-step determination of sampled H 2 O 2 , lactate, and glucose in mouse tumor microdialysate. After optimization of the overall experimental parameters, the system's detection limit reached as low as 0.002 mM for H 2 O 2 , 0.058 mM for lactate, and 0.055 mM for glucose, based on 3 μL of microdialysate, suggesting great potential for determining tumor extracellular concentrations of lactate and glucose. Spike analyses of offline-collected mouse tumor microdialysate and monitoring of the basal concentrations of mouse tumor extracellular H 2 O 2 , lactate, and glucose, as well as those after imparting metabolic disturbance through intra-tumor administration of a glucose solution through a prior-implanted cannula, were conducted to demonstrate the system's applicability. Our results evidently indicate that hyphenation of an MD sampling device with an optimized sequential enzymatic derivatization scheme and a fluorescence spectrometer can be used successfully for multi-analyte monitoring of tumor extracellular metabolites in living animals. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate the value of computed tomography (CT) spectral imaging in assessing the therapeutic efficacy of a vascular endothelial growth factor (VEGF) receptor inhibitor AG-013736 in rabbit VX2 liver tumours.Methods: Twenty-three VX2 liver tumour-bearing rabbits were scanned with CT in spectral imaging mode during the arterial phase (AP) and portal phase (PP). The iodine concentrations(ICs)of tumours normalized to aorta (nICs) at different time points (baseline, 2, 4, 7, 10, and 14 days after treatment) were compared within the treated group (n = 17) as well as between the control (n = 6) and treated groups. Correlations between the tumour size, necrotic fraction (NF), microvessel density (MVD), and nICs were analysed.Results: The change of nICs relative to baseline in the treated group was lower compared to the control group. A greater decrease in the nIC of a tumour at 2 days was positively correlated with a smaller increase in tumour size at 14 days (P < 0.05 for both). The tumour nIC values in AP and PP had correlations with MVD (r = 0.71 and 0.52) and NF (r = -0.54 and -0.51) (P < 0.05 for all).Conclusions: CT spectral imaging allows for the evaluation and early prediction of tumour response to AG-013736.Key Points: • AG-013736 treatment response was evaluated by CT in a rabbit tumour model. • CT spectral imaging allows for the early treatment monitoring of targeted anti-tumour therapies. • Spectral CT findings correlated with vascular changes after anti-tumour therapies. • Spectral CT is a promising method for assessing clinical treatment response. [ABSTRACT FROM AUTHOR]

STAT1/STAT3 transcription factors are important regulators for development of normal, infected or inflammed cells. They are also critically involved in the progression of various malignant tumours, including epithelial-derived carcinomas. Here, we focus on colorectal cancer (CRC) insights for STAT1/3, where controversial functions for STAT3 were reported. For a long time STAT3 has been regarded as a driver of tumour malignancy and its activation was associated with negative clinical outcome. In contrast, STAT1 was generally viewed as an independent tumour suppressor and positive prognostic marker. Here we discuss the experimental evidence for the tight association and regulation of oncogenic STAT3 transcription kept at bay by nuclear STAT1. We summarise current research and describe cellular models of different STAT1/STAT3 expression ratios. STAT1/3 expression levels are influenced by the mutational status of carcinoma cells associated with nuclear unphosphorylated STAT1. Animal tumour models and results from in vitro experiments allow for the conclusion that both proteins interact as antagonistic transcription factors in CRC cells. These STATs steer also important processes during infection and inflammation that influence development and progression of CRC. The STAT1/3 interplay is important to understand gene regulation and we describe it here similar like the YIN/YANG dualism. Thus, we propose to evaluate both STAT1 and STAT3 expression patterns in cancers in a dual manner instead of regarding them as independent transcription factors. This conceptual dualistic view could advance diagnostic predictions in the future. [ABSTRACT FROM AUTHOR]

Cyclophosphamide (CY) is a DNA alkylating agent, which is widely used with other chemotherapy drugs in the treatment of various types of cancer. It can be used not only as a chemotherapeutic but also as an immunomodulatory agent to inhibit IL-10 expression and T regulatory cells (Tregs). Fibroblast activation protein α (FAPα) is expressed in cancer-associated fibroblasts in the tumor microenvironment. Immunotherapy based on FAPα, as a tumor stromal antigen, typically induces specific immune response targeting the tumor microenvironment. This study evaluated the efficacy of a previously unreported CY combination strategy to enhance the limited anti-tumor effect of a DNA vaccine targeting FAPα. The results suggested CY administration could promote the percentage of splenic CD8+ T cells and decrease the proportion of CD4 + CD25 + Foxp3+ Tregs in spleen. In tumor tissues, levels of immunosuppressive cytokines including IL-10 and CXCL-12 were also reduced. Meanwhile, the CY combination did not impair the FAPα-specific immunity induced by the DNA vaccine and further reduced tumor stromal factors. Most importantly, FAP-vaccinated mice also treated with CY chemotherapy showed a marked suppression of tumor growth (inhibition ratio =80%) and a prolongation of survival time. Thus, the combination of FAPα immunotherapy and chemotherapy with CY offers new insights into improving cancer therapies. [ABSTRACT FROM AUTHOR]

Objective A subcutaneous transplantation tumor model of human HT-29 cells was established in nude mice to study the anticarcinogenic activities and apoptosis-regulatory mechanistic effect of aqueous extract of fermented barley with Lactobacillus plantarum dy-1 (LFBE). Methods HT-29 cells were transplanted via subcutaneous injection of 1 × 10 7 cells into the right flank of each nude mouse. Then, nude mice were treated for 30 days with LFBE (high-dose 2 g·kg −1 ·d −1 ; low-dose 1 g·kg −1 ·d −1 ) and for 7 days with 5-fluorouracil (5-FU, 25 g·kg −1 ·d −1 ) by gavage and intraperitoneal injection, respectively. Results Tumor volume and weight decreased significantly in both groups of nude mice treated with LFBE. In addition, the cell apoptosis rate of the LFBE group was significantly higher than that of the control group and 5-FU groups as measured by the TUNEL assay. Moreover, the real-time fluorescent quantitative PCR and Western blot methods further confirmed these apoptosis-enhancing and growth-inhibiting effects. The involvement of LFBE in inducing apoptosis was confirmed by the expression of Bax, Bcl-2, caspase-3, and cyclinD1. Conclusion The results showed that LFBE could induce subcutaneous transplantation tumor apoptosis in nude mice and could be used as a natural nutrient supplement or chemopreventive agent in the treatment of human colon cancer. [ABSTRACT FROM AUTHOR]

The article discusses the use of radical cystectomy as a treatment for non-metastatic muscle-invasive bladder cancer (MIBC) without opting for chemotherapy. It talks about the success of systemic chemotherapy along with drugs like avelumab, brolizumab and durvalumab which are a mixture of immune checkpoint inhibitor (ICI).

Yessotoxins (YTXs) are a group of marine toxins produced by the dinoflagellates Protoceratium reticulatum, Lingulodinium polyedrum and Gonyaulax spinifera. They may have medical interest due to their potential role as anti-allergic but also anti-cancer compounds. However, their biological activities remain poorly characterized. Here, we show that the small molecular compound YTX causes a slight but significant reduction of the ability of mast cells to degranulate. Strikingly, further examination revealed that YTX had a marked and selective cytotoxicity for the RBL-2H3 mast cell line inducing apoptosis, while primary bone marrow derived mast cells were highly resistant. In addition, YTX exhibited strong cytotoxicity against the human B-chronic lymphocytic leukaemia cell line MEC1 and the murine melanoma cell line B16F10. To analyse the potential role of YTX as an anti-cancer drug in vivo we used the well-established B16F10 melanoma preclinical mouse model. Our results demonstrate that a few local application of YTX around established tumours dramatically diminished tumour growth in the absence of any significant toxicity as determined by the absence of weight loss and haematological alterations. Our data support that YTX may have a minor role as an anti-allergic drug, but reveals an important potential for its use as an anti-cancer drug. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma ( NPC) is a refractory tumour, and chemotherapy is one of the primary treatment modalities. Oncoprotein 18 (Op18)/stathmin is a conserved small cytosolic phosphoprotein and highly expressed in tumours, which plays a vital role in maintaining the malignant phenotype of tumours. Taxol is a clinically widely used chemotherapeutic agent for a broad range of taxol-resistant tumours. This study showed that Op18/stathmin silencing by RNA interference ( RNAi) combined taxol cooperatively improved cellular apoptosis in CNE1 cells mainly via initiating endogenous death receptor pathway, impaired the capabilities of cellular proliferation and cellular migration and down-regulated the half maximal inhibitory concentration ( IC50) of taxol, meanwhile decreased the expression of the upstream extracellular regulated kinase 1 ( ERK1) in vitro. Evidence also showed that taxol cytotoxicity was markedly augmented for Op18/stathmin RNAi in other NPC cells. In vivo animal experiments have demonstrated that early combination of Op18/stathmin silencing and taxol evidently inhibited tumourigenicity of CNE1 cells and growth of xenografted tumours in nude mice. Remarkably, silencing Op18/stathmin by RNAi still promoted transformation of late-stage CNE1 cells in NPC-xenografted tumours from moderately to highly differentiated and inhibited the pleiotropic cytokine interleukin-10 ( IL-10) autocrine by transplanted tumours. These findings suggest that silencing Op18/stathmin by RNAi promotes chemosensitization of NPC to taxol and reverses malignant phenotypes of NPC, which provides a new clue for treating drug-resistant tumours. [ABSTRACT FROM AUTHOR]

Morphologically, canine soft-tissue sarcomas (STSs) resemble human STSs. In humans, proper classification of STSs is considered essential to improve insight in the biology of these tumors, and to optimize diagnosis and therapy. To date, there is a paucity of data published on the significance of detailed classification of STSs in the dog. We revised a cohort (n = 110) of proliferative lesions obtained from a study in Golden Retrievers that were considered “soft tissue sarcoma, not otherwise specified or of uncertain subtype” in order to optimize the diagnoses of these lesions. The criteria according to the veterinary WHO classification, recent veterinary literature, and the WHO classification for humans were applied. Revision was initially based on morphologic characteristics of hematoxylin and eosin–stained histologic sections of the neoplasms. If considered necessary (n = 76), additional immunohistochemistry was applied to aid characterization. The diagnosis of STS was confirmed in 75 neoplasms (68%). Of this group, diagnosis of a specific subtype of the STSs was possible in 58 neoplasms. Seven neoplasms had morphologic characteristics that were suggestive for sarcoma subtypes only described in the WHO classification for humans. Seventeen neoplasms remained “unclassified STSs.” Thirty-one lesions (28%) were diagnosed “neoplasm, not being STS.” Four lesions (4%) were considered nonneoplastic. Because incorrect classification of a tumor could lead to inappropriate therapeutic intervention and prognostication, the results of our study clearly illustrate the importance of revision and further diagnosis of “unclassified STSs” in dogs. [ABSTRACT FROM AUTHOR]

The bombesin analogue, [ 99m Tc-GGC]-(Ornithine) 3 -BN(2-14), 99m Tc-BN-O , targeting gastrin releasing peptide receptors (GRPrs) on the surface of tumors, was pre-clinically investigated as potential imaging agent for single photon emission computed tomography (SPECT). In addition, the improvement of its pharmacokinetic profile (PK) was investigated through the co-administration of a succinylated gelatin plasma expander (Gelofusine), aiming to reduce its kidney accumulation and enhance its tumor-to-normal tissue contrast ratios. Biodistribution data were collected from normal mice and rats, and PC-3 tumor bearing mice, in reference to its PK, metabolism and tumor uptake. Imaging data were also collected from PC-3 tumor bearing mice. Biodistribution and imaging experiments showed that 99m Tc-BN-O was able to efficiently localize the tumor (5.23 and 7.00% ID/g at 30 and 60 min post injection, respectively), while at the same time it was rapidly cleared from the circulation through the kidneys. HPLC analysis of kidney samples, collected at 60 min p.i. from normal mice and rats, showed that the majority of radioactivity detected was due to intact peptide i.e. 56% for mice and 73% for rats. Co-administration of 99m Tc-BN-O with Gelo resulted in the reduction of kidney uptake in both animal models. The integrated area under the curve (AUC 30–60 min ) from the concentration–time plots of kidneys was decreased in both mice and rats by 25 and 50%, respectively. In PC-3 tumor bearing mice, an increase of tumor uptake (AUC tumor increased by 69%) was also observed with Gelo. An improvement in tumor-to-blood and tumor-to-normal tissue ratios was noted in all cases with the exception of the pancreas, which normally expresses GRPr. The results of this preclinical study may also be extended to other similar peptides, which are utilized in prostate cancer imaging and present similar PK profile. [ABSTRACT FROM AUTHOR]

Yolk sac carcinoma is an extremely rare tumor in rats and is usually found in the genital system of aged animals. We encountered a yolk sac carcinoma in the pulmonary artery of an 18-week-old female Sprague-Dawley rat. In a repeated dosing toxicity study (once weekly for 4 weeks, intraperitoneal), this rat was unexpectedly found dead on the 55th day after the final administration of the test article. At necropsy, grayish white nodules were found on the lung surface. Histopathologically, tumor emboli were observed in the trunk and branch of the pulmonary artery. Tumor cells with slightly basophilic vacuolated cytoplasm and large vesicular nuclei formed nests or clusters and were embedded in a homogenous eosinophilic and periodic acid-Schiff reaction positive matrix. The tumor cells and matrix were immunoreactive for laminin. The embolic tumor resembled yolk sac carcinoma showing a parietal pattern in rodents. Although the primary site was unknown, the tumor was considered to be a metastatic yolk sac carcinoma. [ABSTRACT FROM AUTHOR]

Two fluorescent chemosenors, Mito-HS and Lyso-HS, were rationally designed and synthesized with positive charge at physiological conditions. The positive charge showed triple functions as target moieties for subcellular mitochondria and lysosome of living cells, soluble moieties for chemosenors, as well as effective sequesters of HS-(H2S at physiological conditions). These two probes showed faster and more efficient fluorescence H2S detection than the similar literature-reported probe without positive charge. In addition, visualizing of hydrogen sulfide in tumors of living mice was successfully achieved for the first time using the probe Mito-HS. [ABSTRACT FROM AUTHOR]

A positive modulation of immune system is necessary for preparing the body to fight against malignant tumor cells. In the present study, the stimulatory effect of Curculigoside on cell-mediated immune response against the metastasis of B16F10 melanoma cells was analyzed in C57BL/6 mice. Curculigoside is a phenolic glucoside present in the plantCurculigo orchioidesGaertn. (Family – Amaryllidaceae). Administration of Curculigoside enhanced the natural killer (NK) cell activity, antibody-dependent cell-mediated cytotoxicity and complement-mediated cytotoxicity in metastatic tumor-bearing animals, when compared to the untreated control animals. The compound was also found to be effective in reducing the levels of proinflammatory cytokines such as TNF-α, IL-1β, IL-6 and GM-CSF during metastasis. Besides these, levels of TH1 cytokines, such as IL-2 and IFN-γ, were significantly enhanced (p < 0.001) by Curculigoside administration and thereby reduces the metastatic lung colony formation along with an increased lifespan of the experimental animals. These studies provide an evidence for the stimulation of cell-mediated immune responses by Curculigoside against B16F10-induced metastatic tumor progression in experimental animals. [ABSTRACT FROM PUBLISHER]

The purpose of this study was to investigate (1) the impact of tumor growth on homocysteine (Hcy) metabolism, liver oxidative stress and cancer cachexia and, (2) the potential benefits of creatine supplementation in Walker-256 tumor-bearing rats. Three experiments were conducted. First, rats were killed on days 5 (D5), 10 (D10) and 14 (D14) after tumor implantation. In experiment 2, rats were randomly assigned to three groups designated as control (C), tumor-bearing (T) and tumor-bearing supplemented with creatine (TCr). A life span experiment was conducted as the third experiment. Creatine was supplied in drinking water for 21 days (8 g/L) in all cases. Tumor implantation consisted of a suspension of Walker-256 cells (8.0 × 10 cells in 0.5 mL of PBS). The progressive increase ( P < 0.05) in tumor mass coincided with a progressively lower body weight and higher hepatic oxidative stress; plasma Hcy concentration was 80 % higher ( P < 0.05) by 10 days of tumor implantation. Impaired Hcy metabolism was evidenced by decreased hepatic betaine-homocysteine methyltransferase (Bhmt), glycine N-methyltransferase (Gnmt) and cystathionine beta synthase (CBS) gene expression. In contrast, creatine supplementation promoted a 28 % reduction of tumor weight ( P < 0.05). Plasma Hcy (C 6.1 ± 0.6, T 10.3 ± 1.5, TCr 6.3 ± 0.9, µmol/L) and hepatic oxidative stress were lower in the TCr group compared to T. Creatine supplementation was unable to decrease Hcy concentration and to increase SAM/SAH ratio in tumor tissue. These data suggest that creatine effects on hepatic impaired Hcy metabolism promoted by tumor cell inoculation are responsible to decrease plasma Hcy in tumor-bearing rats. In conclusion, Walker-256 tumor growth is associated with progressive hyperhomocysteinemia, body weight loss and liver oxidative stress in rats. Creatine supplementation, however, prevented these tumor-associated perturbations. [ABSTRACT FROM AUTHOR]

Although some physiological and pathological function parameters of hepatitis and liver cancer have been investigated in relation to hispidulin (5,7,4′-trihydroxy-6-methoxyflavone), the changes of small metabolites in biofluids have been reported rarely. Recent research has shown that metabolic profiling with ultra-high-performance liquid chromatography coupled to quadrupole time of flight mass spectrometry (UHPLC-QTOF/MS) coupled with multivariate statistical analysis provides a good understanding of hispidulin effects on mice vaccinated intraperitoneally with H 22 tumor cells. Twenty-five potential biomarkers, up- or down-regulated ( P < 0.05 or 0.01), were identified, and 17 metabolic pathways were constructed. These potential biomarkers underpin the metabolic pathways, which are disturbed in the mice bearing neoplasm (H 22 ). These pathways include pantothenate and CoA biosynthesis; glycine, serine and threonine metabolism; nicotinate and nicotinamide metabolism; steroid hormone biosynthesis; pyrimidine metabolism; and glyoxylate and dicarboxylate metabolism. Furthermore, 4-phosphopantothenoylcysteine, glycine, niacinamide, cortisol, uracil and 5-thymidylic acid are potential biomarkers that may explain the link between hispidulin and the metabolism of mice bearing neoplasm (H 22 ). Most of the potential biomarkers related to the function of TCA (tricarboxylic acid cycle). The rise of potential biomarkers in the drug groups promoted the up-regulation of TCA cycle compared with the model group. [ABSTRACT FROM AUTHOR]

Background: The Animals in Research: Reporting In Vivo Experiments (ARRIVE) guidelines were published in 2010 with the aim of improving the quality of studies involving animals. However, how well Chinese studies involving animal neoplasms adhere to these guidelines has not been assessed. Objective: To evaluate the reporting quality of such experiments published between 2010 and 2012 in Chinese journals with support from the National Natural Science Foundation of China. Methods: We searched the Chinese Science Citation and Chinese Journal Full-Text Databases for articles published between 2010 and 2012 involving neoplasms in animals. The data were extracted into pre-prepared forms. Reporting quality was assessed using the ARRIVE checklist—39 items plus information on blinding. Results: Three hundred and ninety-six animal studies were included in the analysis: 127 studies published in 2010, 140 studies published in 2011, and 129 studies published in 2012. The range of ARRIVE score is from 12 to 27 with a maximum possible score of 40. Studies published in 2012 (P = 0.012), 2011 (P = 0.015), 2010, July~Dec (P<0.017) had a significantly larger ARRIVE checklist score than those published in Jan.~June, 2010, respectively. Conclusions: Experiments involving neoplasms in animals published in Chinese journals generally have not comprehensively reported the information recommended by the ARRIVE guidelines. We strongly recommend that researchers conducting such studies report this information. [ABSTRACT FROM AUTHOR]

A central resistance mechanism in solid tumors is the maintenance of epithelial junctions between malignant cells that prevent drug penetration into the tumor. Human adenoviruses (Ads) have evolved mechanisms to breach epithelial barriers. For example, during Ad serotype 3 (Ad3) infection of epithelial tumor cells, massive amounts of subviral penton-dodecahedral particles (PtDd) are produced and released from infected cells to trigger the transient opening of epithelial junctions, thus facilitating lateral virus spread. We show here that an Ad3 mutant that is disabled for PtDd production is significantly less effective in killing of epithelial human xenograft tumors than the wild-type Ad3 virus. Intratumoral spread and therapeutic effect of the Ad3 mutant was enhanced by co-administration of a small recombinant protein (JO; produced in Escherichia coli) that incorporated the minimal junction opening domains of PtDd. We then demonstrated that co-administration of JO with replication-competent Ads that do not produce PtDd (Ad5, Ad35) resulted in greater attenuation of tumor growth than virus injection alone. Furthermore, we genetically modified a conditionally replicating Ad5-based oncolytic Ad (Ad5Δ24) to express a secreted form of JO upon replication in tumor cells. The JO-expressing virus had a significantly greater antitumor effect than the unmodified AdΔ24 version. Our findings indicate that epithelial junctions limit the efficacy of oncolytic Ads and that this problem can be address by co-injection or expression of JO. JO has also the potential for improving cancer therapy with other types of oncolytic viruses. [ABSTRACT FROM AUTHOR]

Tb represents a powerful alternative to currently used α-emitters: the relatively short half-life (T = 4.1 h), low α-energy (3.97 MeV, I = 16.7 %), absence of α-emitting daughters and stable coordination via DOTA are favorable features for potential clinical application. In this letter, we wish to highlight the unique characteristics of Tb for PET imaging, based on its positron emission (E = 730 keV, I = 7.1 %) in addition to it's a therapeutic value. To this end, a preclinical study with a tumor-bearing mouse is presented. The perspective of alpha-PET makes Tb highly appealing for radiotheragnostic applications in future clinical trials. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study is to investigate whether changes could be detected in dynamic contrast-enhanced (DCE) and intra-voxel incoherent motion (IVIM) MR parameters upon MR-guided high-intensity focused ultrasound (MR-HIFU)-induced hyperthermia in a rabbit Vx2 tumor model. Methods: Five Vx2 tumor-bearing New Zealand white rabbits were treated with hyperthermia using a clinical MR-HIFU system. Data were acquired before and after hyperthermia. For the DCE analysis, the extended Tofts model was used. For the IVIM analysis, a Bayesian approach was used. Maps were reconstructed of the DCE parameters (Ktrans, kep, and vp) and IVIM parameters (Dt, fp, and Dp). Individual parameter histograms and two-dimensional cross-correlation histograms were constructed to analyze changes in the parameters after hyperthermia. Changes in median values were tested for statistical significance with the Mann-Whitney U test. Results: The MR temperature measurements confirmed that mild hyperthermia (40 to 42 °C) was successfully achieved in all rabbits. One rabbit died during treatment and was excluded from the analysis. In the remaining four rabbits, an increase in Dt was observed. In three rabbits, an increase in Ktrans was observed, while in the other rabbits, all three DCE parameter values decreased. Mixed changes were seen for vp and fp. Conclusions: Changes in DCE and IVIM parameters were detected after hyperthermia and were variable between the rabbits. DCE- and IVIM-MRI may be promising tools to assess tumor responses to hyperthermia. Further research in a larger number of subjects is necessary in order to assess their value for treatment response monitoring. [ABSTRACT FROM AUTHOR]

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that promote tumor progression. In this study, we demonstrated that activation of a C-type lectin receptor, dectin-1, in MDSC differentially modulates the function of different MDSC subsets. Yeast-derived whole β-glucan particles (WGP; a ligand to engage and activate dectin-1, oral treatment in vivo) significantly decreased tumor weight and splenomegaly in tumor-bearing mice with reduced accumulation of polymorphonuclear MDSC but not monocytic MDSC (M-MDSC), and decreased polymorphonuclear MDSC suppression in vitro through the induction of respiratory burst and apoptosis. On a different axis, WGP-treated M-MDSC differentiated into F4/80+CD11c+ cells in vitro that served as potent APC to induce Ag-specific CD4+ and CD8+ T cell responses in a dectin-1-dependent manner. Additionally, Erk1/2 phosphorylation was required for the acquisition of APC properties in M-MDSC. Moreover, WGP-treated M-MDSC differentiated into CD11c+ cells in vivo with high MHC class II expression and induced decreased tumor burden when inoculated s.c. with Lewis lung carcinoma cells. This effect was dependent on the dectin-1 receptor. Strikingly, patients with non-small cell lung carcinoma that had received WGP treatment for 10-14 d prior to any other treatment had a decreased frequency of CD14-HLA-DR-CD11b+CD33+ MDSC in the peripheral blood. Overall, these data indicate that WGP may be a potent immune modulator of MDSC suppressive function and differentiation in cancer. [ABSTRACT FROM AUTHOR]

The role of Ras in human skin tumorigenesis induction is still ambiguous. Overexpression of oncogenic Ras causes premature senescence in cultured human cells and hyperplasia in transgenic mice. Here, we investigated whether the oncogenic insult outcome might depend on the nature of the founding keratinocyte. We demonstrate that overexpression of the constitutively active Ras-V12 induces senescence in primary human keratinocyte cultures, but that some cells escape senescence and proliferate indefinitely. Ras overexpression in transient-amplifying- or stem-cell-enriched cultures shows that p16 (encoded by CDKN2A) levels are crucial for the final result. Indeed, transient-amplifying keratinocytes expressing high levels of p16 are sensitive to Ras-V12-induced senescence, whereas cells with high proliferative potential, but that do not display p16, are resistant. The subpopulation that sustains the indefinite culture growth exhibits stem cell features. Bypass of senescence correlates with inhibition of the pRb (also known as RB1) pathway and resumption of telomerase reverse transcriptase (TERT) activity. Immortalization is also sustained by activation of the ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1) and Akt pathways. Moreover, only transduced cultures originating from cultures bearing stem cells induce tumors in nude mice. Our findings demonstrate that the Ras overexpression outcome depends on the clonogenic potential of the recipient keratinocyte and that only the stem cell compartment is competent to initiate tumorigenesis. [ABSTRACT FROM AUTHOR]

The antitumor function of fungal polysaccharides is a popular area of interest in the research field due to their high efficiency and low side effects. The main mechanism of fungal polysaccharides is immune enhancement. The polysaccharose (APS-3) was extracted from the fruit body of Phellinus pullus. The proliferation inhibition to mouse sarcoma 180 (S180) tumor cells was studied by the MTT method. Mice models of transplanted S180 tumor were established and treated with APS-3 to verify the antitumor activity in vivo. Natural killer (NK) and lymphokine-activated killer (LAK) cytotoxicities of the mice were evaluated by the lactate dehydrogenase method. APS-3 can significantly inhibit the proliferation of the S180 cells. Cells could be completely inhibited by 1.6 mg/ml APS-3 after 24 h treatment. After 18 days of treatment, the antitumor rate of the high-dose group was 85.47%. Histopathology detection showed that for the APS-3-treated mice, the tumor cells dissolved, and exhibited a large range of structureless necrotic areas. NK and LAK cytotoxicities of the APS-3 treated mice increased by 61.85 and 56.16%, respectively, compared with the normal control mice. APS-3 can be used as an antitumor agent by way of immune enhancement. [ABSTRACT FROM AUTHOR]

Transcriptional factor FOXC1 has been demonstrated to play a key role in embryogenesis in animal studies and may participate in tumorigenesis. However, the specific function of this gene in ovarian tumors has not been fully determined. In this study, potential correlations between FOXC1 expression and clinicopathological features of serous ovarian tumors were investigated. FOXC1 expression was analyzed in SKOV-3 and HO-8910 cell lines and serous ovarian tumor tissues. A significant correlation was observed between FOXC1 protein expression and pathological subtype as well as FIGO stage (P<0.05) in serous ovarian tumors in our retrospective study. No significant association was revealed between FOXC1 protein expression and the clinicopathological factors of age, histological grade and volume of ascites (P>0.05). The results suggest that high expression of FOXC1 protein may serve as a marker for benign serous ovarian tumors and a suggest a trend towards good prognosis. [ABSTRACT FROM AUTHOR]

The design and construction of nanoreactors are important for biomedical applications of enzymes, but lipidand polymeric-vesicle-based nanoreactors have some practical limitations. We have succeeded in preparing enzyme-loaded polyion complex vesicles (PICsomes) through a facile proteinloading method. The preservation of enzyme activity was confirmed even after cross-linking of the PICsomes. The crosslinked b-galactosidase-loaded PICsomes (β-gal@PICsomes) selectively accumulated in the tumor tissue of mice. Moreover, a model prodrug, HMDER-βGal, was successfully converted into a highly fluorescent product, HMDER, at the tumor site, even 4 days after administration of the β-gal@PICsomes. Intravital confocal microscopy showed continuous production of HMDER and its distribution throughout the tumor tissues. Thus, enzyme-loaded PICsomes are useful for prodrug activation at the tumor site and could be a versatile platform for enzyme delivery in enzyme prodrug therapy. [ABSTRACT FROM AUTHOR]

Adoptive cell transfer (ACT) of purified naive, stem cell memory, and central memory T cell subsets results in superior persistence and antitumor immunity compared with ACT of populations containing more-differentiated effector memory and effector T cells. Despite a clear advantage of the less-differentiated populations, the majority of ACT trials utilize unfractionated T cell subsets. Here, we have challenged the notion that the mere presence of less-differentiated T cells in starting populations used to generate therapeutic T cells is sufficient to convey their desirable attributes. Using both mouse and human cells, we identified a T cell-T cell interaction whereby antigen-experienced subsets directly promote the phenotypic, functional, and metabolic differentiation of naive T cells. This process led to the loss of less-differentiated T cell subsets and resulted in impaired cellular persistence and tumor regression in mouse models following ACT. The T memory-induced conversion of naive T cells was mediated by a nonapoptotic Fas signal, resulting in Akt-driven cellular differentiation. Thus, induction of Fas signaling enhanced T cell differentiation and impaired antitumor immunity, while Fas signaling blockade preserved the antitumor efficacy of naive cells within mixed populations. These findings reveal that T cell subsets can synchronize their differentiation state in a process similar to quorum sensing in unicellular organisms and suggest that disruption of this quorum-like behavior among T cells has potential to enhance T cell-based immunotherapies. [ABSTRACT FROM AUTHOR]

Background: Dendritic cell (DC)-based vaccination has shown promising application in tumor immunotherapy. However, it is not clear whether the presence of tumor impacts the efficacy of generation and functionality of DCs. Aim: To compare the phenotype of DCs generated from naïve or tumor bearing mice and their capability to restore leukopenia-associated chemotherapy. Materials and Methods: DCs were generated from bone marrow (BM) of naïve or Ehrlich ascites carcinoma (EAC) bearing mice. EAC is an undifferentiated breast cancer cell line with the high transplantable capability and rapid proliferation. BM cells were cultured in vitro for 7 days with granulocyte macrophage colony-stimulating factor and interleukin-4 (20 ng/ml each), loaded with different concentrations of EAC cell lysate (0.5, 1, 3 and 5 mg/106 ) DCs followed by activation with the toll-like receptor 3 ligand poly(I:C). For DC-based vaccination, CD1 mice (n = 5/group) were inoculated with an intraperitoneal (i.p.) injection of 0.25 x 106 EAC cells to form ascites, treated on day 14 with an i.p. injection of cyclophosphamide (4 mg/mouse) and on day 15 with subcutaneous injection of 2 x 106 DCs from control or EAC bearing mice. Injected DCs were loaded with or without EAC lysate followed by i.p. injection of 50 µg/mouse poly(I:C). On day 21, mice were bled and sacrificed for peripheral blood count and spleen and BM cellularity. Results: Yield of DCs generated from naïve or EAC bearing mice, as well as their phenotype (CD11c+ CD11b+ ) and activation (CD40 and CD80) with poly(I:C) were similar . Loading DCs with 1 mg EAC lysate induced better viability and activation phenotype as compared with the other concentrations. Regardless the source of DCs, DCs vaccination restored the total numbers of leukocytes in blood but not in the spleen and BM. The effect on peripheral blood leukocytes was coincided with the restoration of the relative numbers of lymphocytes, monocytes, and granulocytes. Conclusion: These data support the use of allogenic DCs from healthy donors in anticancer DC-based vaccination. [ABSTRACT FROM AUTHOR]

Primary ovarian tumors are generally uncommon in rats used in toxicologic studies. A malignant Sertoli cell tumor was present in the ovary of a 19-week-old female Sprague Dawley rat. Macroscopically, the mass was white and firm, 10 × 13 × 17 mm in size, and located in the right ovary. Histopathologically, the mass was composed of nests of pleomorphic cells, which formed seminiferous-like tubules separated by a thin fibrovascular stroma. The tubules were lined by tumor cells, which had basally located nuclei and abundant eosinophilic and vacuolated cytoplasm. In some areas, the tumor cells were arranged in a retiform growth pattern, mimicking a rete testis/ovarii. Disseminated metastases to the surfaces of the mesentery, spleen and liver were also present. Immunohistochemically, many tumor cells were strongly positive for vimentin, estrogen receptor α and Ki 67. Some tumor cells were positive for pancytokeratin and inhibin α. These findings closely resemble those of an ovarian-derived human malignant Sertoli cell tumor. From our review of the literature, we believe this is the first report of a spontaneous malignant Sertoli cell tumor in the ovary of a young laboratory rat. This case might provide useful historical control information for rat toxicity studies. [ABSTRACT FROM AUTHOR]

Background: Ginseng is Chinese traditional herbal medicine, and the ginsenoside Rg3 is the main bioactive ingredient for the anti-tumor effect. However, there is no study on pharmacokinetics (PKs) of ginsenoside Rg3 and its main metabolite after oral ginsenoside Rg3 in tumor-bearing plasma. The aim of this study was to investigate the PK profiles of ginsenoside Rg3 and ginsenoside Rh2 after oral administration of pure ginsenoside Rg3 were administered, and compare the difference of the PK profiles between normal and Walker 256 tumor-bearing rats. Materials and Methods: The concentrations of two ginsenosides in plasma were determined by using a simple and rapid high-performance liquid chromatography. All the rats were divided randomly into two groups (Walker 256 tumor-bearing and normal groups). Each group received oral administration of 50 mg/kg ginsenoside Rg3. Results: The results showed that ginsenoside Rh2, possibly as a glycosylation hydrolysis product of ginsenoside Rg3, were found in plasma after oral administration of ginsenoside Rg3 to rats. Ginsenoside Rg3 had shown better absorption than ginsenoside Rh2, whether the oral administration of ginsenoside Rg3, normal rats showed better absorption than tumor-bearing rats. Discussion and Conclusion: The PKs properties of the ginsenoside Rg3 and ginsenoside Rh2 differed between tumor-bearing rats and normal rats, including area under the plasma level/time curve and concentration maximum (P < 0.05). [ABSTRACT FROM AUTHOR]

Ligand-mediated targeting of anticancer therapeutic agents is a useful strategy for improving anti-tumor efficacy. It has been reported that co-administration of a tumor-penetrating peptide iRGD (CRGDK/RGPD/EC) enhances the efficacy of anticancer drugs. Here, we designed an experiment involving co-administration of iRGD-SSL-DOX with free iRGD to B16-F10 tumor bearing mice to examine the action of free iRGD. We also designed an experiment to investigate the location of iRGD-modified SSL when co-administered with free iRGD or free RGD to B16-F10 tumor bearing nude mice. Considering the sequence of iRGD, we selected the GPDC, RGD and CRGDK as targeting ligands to investigate the targeting effect of these peptides compared with iRGD on B16-F10 and MCF-7 cells, with or without enzymatic degradation. Finally, we selected free RGD, free CRGDK and free iRGD as ligand to investigate the inhibitory effect on RGD-, CRGDK- or iRGD-modified SSL on B16-F10 or MCF-7 cells. Our results indicated that iRGD targeting to tumor cells was ligand–receptor mediated involving RGD to αv-integrin receptor and CRGDK to NRP-1 receptor. Being competitive effect, the administration of free iRGD would not be able to further enhance the anti-tumor activity of iRGD-modified SSL. There is no need to co-administrate of free iRGD with the iRGD-modified nanoparticles for further therapeutic benefit. [ABSTRACT FROM PUBLISHER]