Model of MM Cell BM-homing Using Zebrafish

Advancement of many solid tumors and hematologic malignancies is frequently characterized by dissemination and homing of cancer cells to the bone marrow (BM). Methods to quantitatively characterize these key steps of the metastatic cascade in mammalian models are currently limited and do not offer opportunities to perform rapid, large-scale genomic, or drug screening. Because of their optical clarity, we used zebrafish to develop an in vivo model of cancer cell dissemination and homing to the BM. We performed intracardiac injection of multiple myeloma (MM) cells derived from human BM or cell lines and monitored their migration to the caudal hematopoietic tissue (CHT), the region where hematopoiesis occurs in the zebrafish embryo, which recapitulates a BM-like niche. Transcriptomic analyses confirmed that MM cells homing to the CHT displayed gene-expression differences compared with MM cells outside of the CHT, including significant enrichment for genes known to regulate interleukin-6 (IL6) signaling, cell adhesion, and angiogenesis. Collectively, our findings point to the zebrafish as a valuable model in which to study cancer cell homing to the hematopoietic niche and to establish a screening platform for the identification of factors and mechanisms contributing to the early steps of bone metastasis. Cancer Res; 76(2); 463–71. ©2016 AACR.

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Novel Survivin Protein Inhibitors

Many oncoproteins are considered undruggable because they lack enzymatic activities. In this study, we present a small-molecule–based anticancer agent that acts by inhibiting dimerization of the oncoprotein survivin, thereby promoting its degradation along with spontaneous apoptosis in cancer cells. Through a combination of computational analysis of the dimerization interface and in silico screening, we identified one compound that induced proteasome-dependent survivin degradation. Analysis of a set of structural analogues led us to identify a lead compound (LQZ-7F), which was effective in blocking the survival of multiple cancer cell lines in a low micromolar concentration range. LQZ-7F induced proteasome-dependent survivin degradation, mitotic arrest, and apoptosis, and it blocked the growth of human tumors in mouse xenograft assays. In addition to providing preclinical proof of concept for a survivin-targeting anticancer agent, our work offers novel in silico screening strategies to therapeutically target homodimeric oncogenic proteins considered undruggable. Cancer Res; 76(2); 453–62. ©2016 AACR.

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Anti-PD-L1 Antibody Imaging, Biodistribution, and Dosimetry

The programmed cell death ligand 1 (PD-L1) participates in an immune checkpoint system involved in preventing autoimmunity. PD-L1 is expressed on tumor cells, tumor-associated macrophages, and other cells in the tumor microenvironment. Anti–PD-L1 antibodies are active against a variety of cancers, and combined anti–PD-L1 therapy with external beam radiotherapy has been shown to increase therapeutic efficacy. PD-L1 expression status is an important indicator of prognosis and therapy responsiveness, but methods to precisely capture the dynamics of PD-L1 expression in the tumor microenvironment are still limited. In this study, we developed a murine anti–PD-L1 antibody conjugated to the radionuclide Indium-111 (111In) for imaging and biodistribution studies in an immune-intact mouse model of breast cancer. The distribution of 111In-DTPA-anti-PD-L1 in tumors as well as the spleen, liver, thymus, heart, and lungs peaked 72 hours after injection. Coinjection of labeled and 100-fold unlabeled antibody significantly reduced spleen uptake at 24 hours, indicating that an excess of unlabeled antibody effectively blocked PD-L1 sites in the spleen, thus shifting the concentration of 111In-DTPA-anti-PD-L1 into the blood stream and potentially increasing tumor uptake. Clearance of 111In-DTPA-anti-PD-L1 from all organs occurred at 144 hours. Moreover, dosimetry calculations revealed that radionuclide-labeled anti–PD-L1 antibody yielded tolerable projected marrow doses, further supporting its use for radiopharmaceutical therapy. Taken together, these studies demonstrate the feasibility of using anti–PD-L1 antibody for radionuclide imaging and radioimmunotherapy and highlight a new opportunity to optimize and monitor the efficacy of immune checkpoint inhibition therapy. Cancer Res; 76(2); 472–9. ©2015 AACR.

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Albumin-Bound Paclitaxel Loaded in Multistage Vector for Liver Mets

Current treatments for liver metastases arising from primary breast and lung cancers are minimally effective. One reason for this unfavorable outcome is that liver metastases are poorly vascularized, limiting the ability to deliver therapeutics from the systemic circulation to lesions. Seeking to enhance transport of agents into the tumor microenvironment, we designed a system in which nanoparticle albumin-bound paclitaxel (nAb-PTX) is loaded into a nanoporous solid multistage nanovector (MSV) to enable the passage of the drug through the tumor vessel wall and enhance its interaction with liver macrophages. MSV enablement increased nAb-PTX efficacy and survival in mouse models of breast and lung liver metastasis. MSV-nAb-PTX also augmented the accumulation of paclitaxel and MSV in the liver, specifically in macrophages, whereas paclitaxel levels in the blood were unchanged after administering MSV-nAb-PTX or nAb-PTX. In vitro studies demonstrated that macrophages treated with MSV-nAb-PTX remained viable and were able to internalize, retain, and release significantly higher quantities of paclitaxel compared with treatment with nAb-PTX. The cytotoxic potency of the released paclitaxel was also confirmed in tumor cells cultured with the supernatants of macrophage treated with MSV-nAB-PTX. Collectively, our findings showed how redirecting nAb-PTX to liver macrophages within the tumor microenvironment can elicit a greater therapeutic response in patients with metastatic liver cancer, without increasing systemic side effects. Cancer Res; 76(2); 429–39. ©2016 AACR.

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NRP2 Axis and Endosome Maturation

Neuropilin-2 (NRP2) is a non-tyrosine kinase receptor frequently overexpressed in various malignancies, where it has been implicated in promoting many protumorigenic behaviors, such as imparting therapeutic resistance to metastatic cancer cells. Here, we report a novel function of NRP2 as a regulator of endocytosis, which is enhanced in cancer cells and is often associated with increased metastatic potential and drug resistance. We found that NRP2 depletion in human prostate and pancreatic cancer cells resulted in the accumulation of EEA1/Rab5-positive early endosomes concomitant with a decrease in Rab7-positive late endosomes, suggesting a delay in early-to-late endosome maturation. NRP2 depletion also impaired the endocytic transport of cell surface EGFR, arresting functionally active EGFR in endocytic vesicles that consequently led to aberrant ERK activation and cell death. Mechanistic investigations revealed that WD-repeat– and FYVE-domain–containing protein 1 (WDFY1) functioned downstream of NRP2 to promote endosome maturation, thereby influencing the endosomal trafficking of EGFR and the formation of autolysosomes responsible for the degradation of internalized cargo. Overall, our results indicate that the NRP2/WDFY1 axis is required for maintaining endocytic activity in cancer cells, which supports their oncogenic activities and confers drug resistance. Therefore, therapeutically targeting endocytosis may represent an attractive strategy to selectively target cancer cells in multiple malignancies. Cancer Res; 76(2); 418–28. ©2015 AACR.

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Targeting TORC1/2 and Notch1 Abrogates Tumor Initiation

Approximately 30% of triple-negative breast cancers (TNBC) harbor molecular alterations in PI3K/mTOR signaling, but therapeutic inhibition of this pathway has not been effective. We hypothesized that intrinsic resistance to TORC1/2 inhibition is driven by cancer stem cell (CSC)-like populations that could be targeted to enhance the antitumor action of these drugs. Therefore, we investigated the molecular mechanisms by which PI3K/mTOR inhibitors affect the stem-like properties of TNBC cells. Treatment of established TNBC cell lines with a PI3K/mTOR inhibitor or a TORC1/2 inhibitor increased the expression of CSC markers and mammosphere formation. A CSC-specific PCR array revealed that inhibition of TORC1/2 increased FGF1 and Notch1 expression. Notch1 activity was also induced in TNBC cells treated with TORC1/2 inhibitors and associated with increased mitochondrial metabolism and FGFR1 signaling. Notably, genetic and pharmacologic blockade of Notch1 abrogated the increase in CSC markers, mammosphere formation, and in vivo tumor-initiating capacity induced by TORC1/2 inhibition. These results suggest that targeting the FGFR–mitochondrial metabolism–Notch1 axis prevents resistance to TORC1/2 inhibitors by eradicating drug-resistant CSCs in TNBC, and may thus represent an attractive therapeutic strategy to improve drug responsiveness and efficacy. Cancer Res; 76(2); 440–52. ©2015 AACR.

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BRAF/PI3K{beta}/IGF1R Inhibitor Synergy in PTENLOF/BRAFMUT Melanoma

The introduction of MAPK pathway inhibitors paved the road for significant advancements in the treatment of BRAF-mutant (BRAFMUT) melanoma. However, even BRAF/MEK inhibitor combination therapy has failed to offer a curative treatment option, most likely because these pathways constitute a codependent signaling network. Concomitant PTEN loss of function (PTENLOF) occurs in approximately 40% of BRAFMUT melanomas. In this study, we sought to identify the nodes of the PTEN/PI3K pathway that would be amenable to combined therapy with MAPK pathway inhibitors for the treatment of PTENLOF/BRAFMUT melanoma. Large-scale compound sensitivity profiling revealed that PTENLOF melanoma cell lines were sensitive to PI3Kβ inhibitors, albeit only partially. An unbiased shRNA screen (7,500 genes and 20 shRNAs/genes) across 11 cell lines in the presence of a PI3Kβ inhibitor identified an adaptive response involving the IGF1R–PI3Kα axis. Combined inhibition of the MAPK pathway, PI3Kβ, and PI3Kα or insulin-like growth factor receptor 1 (IGF1R) synergistically sustained pathway blockade, induced apoptosis, and inhibited tumor growth in PTENLOF/BRAFMUT melanoma models. Notably, combined treatment with the IGF1R inhibitor, but not the PI3Kα inhibitor, failed to elevate glucose or insulin signaling. Taken together, our findings provide a strong rationale for testing combinations of panPI3K, PI3Kβ + IGF1R, and MAPK pathway inhibitors in PTENLOF/BRAFMUT melanoma patients to achieve maximal response. Cancer Res; 76(2); 390–402. ©2015 AACR.

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Molecular Targets of Tumor Dissemination

Peritonitis carcinomatosa is an advanced and intractable state of gastrointestinal and ovarian cancer, where mechanistic elucidation might enable the development of more effective therapies. Peritoneal dissemination of this type of malignancy has been generally thought to initiate from "milky spots" of primitive lymphoid tissues in the peritoneal cavity. In this study, we offer evidence challenging this idea, based on the finding that tumor implantation and directional dissemination was not required for the presence of milky spots, but rather SCF/CXCL12–expressing niche-like cells located at the border regions of perivascular adipose tissue. Interestingly, we found that peritoneal cavity lavage fluid, which specifically contains peritoneal collagen type IV and plasma fibronectin, dramatically facilitated spheroid formation of murine and human colon cancer cells. Spheroid formation strongly induced the expression of CXCR4 in an Sp1-dependent manner to promote niche-directed metastasis. Notably, disrupting sphere formation or inhibiting Sp1 activity was sufficient to suppress tumor dissemination and potentiated chemosensitivity to 5-fluorouracil. Our findings illuminate mechanisms of peritoneal cancer dissemination and highlight the Sp1/CXCR4/CXCL12 signaling axis as a rational target for the development of therapeutics to manage this intractable form of malignancy. Cancer Res; 76(2); 347–57. ©2016 AACR.

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Melanoma Phenotype-Dependent Mast Cell Recruitment

Human melanomas exhibit considerable genetic, pathologic, and microenvironmental heterogeneity. Genetically engineered mice have successfully been used to model the genomic aberrations contributing to melanoma pathogenesis, but their ability to recapitulate the phenotypic variability of human disease and the complex interactions with the immune system have not been addressed. Here, we report the unexpected finding that immune cell–poor pigmented and immune cell–rich amelanotic melanomas developed simultaneously in Cdk4R24C-mutant mice upon melanocyte-specific conditional activation of oncogenic BrafV600E and a single application of the carcinogen 7,12-dimethylbenz(a)anthracene. Interestingly, amelanotic melanomas showed morphologic and molecular features of malignant peripheral nerve sheath tumors (MPNST). A bioinformatic cross-species comparison using a gene expression signature of MPNST-like mouse melanomas identified a subset of human melanomas with a similar histomorphology. Furthermore, this subset of human melanomas was found to be highly associated with a mast cell gene signature, and accordingly, mouse MPNST-like melanomas were also extensively infiltrated by mast cells and expressed mast cell chemoattractants similar to human counterparts. A transplantable mouse MPNST-like melanoma cell line recapitulated mast cell recruitment in syngeneic mice, demonstrating that this cell state can directly reconstitute the histomorphologic and microenvironmental features of primary MPNST-like melanomas. Our study emphasizes the importance of reciprocal, phenotype-dependent melanoma–immune cell interactions and highlights a critical role for mast cells in a subset of melanomas. Moreover, our BrafV600E-Cdk4R24C model represents an attractive system for the development of therapeutic approaches that can target the heterogeneous tumor microenvironment characteristic of human melanomas. Cancer Res; 76(2); 251–63. ©2015 AACR.

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Cyclin D1 and DNA Damage Sensing

Therapy resistance and poor outcome in prostate cancer is associated with increased expression of cyclin D1. Androgens promote DNA double-strand break repair to reduce DNA damage, and cyclin D1 was also shown to enhance DNA damage repair (DDR). In this study, we investigated the significance of cyclin D1 in androgen-induced DDR using established prostate cancer cells and prostate tissues from cyclin D1 knockout mice. We demonstrate that endogenous cyclin D1 further diminished the dihydrotestosterone (DHT)-dependent reduction of γH2AX foci in vitro. We also show that cyclin D1 was required for the androgen-dependent DNA damage response both in vitro and in vivo. Furthermore, cyclin D1 was required for androgen-enhanced DDR and radioresistance of prostate cancer cells. Moreover, microarray analysis of primary prostate epithelial cells from cyclin D1-deficient and wild-type mice demonstrated that most of the DHT-dependent gene expression changes are also cyclin D1 dependent. Collectively, our findings suggest that the hormone-mediated recruitment of cyclin D1 to sites of DDR may facilitate the resistance of prostate cancer cells to DNA damage therapies and highlight the need to explore other therapeutic approaches in prostate cancer to prevent or overcome drug resistance. Cancer Res; 76(2); 329–38. ©2015 AACR.

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IL21 Signaling in Anti-ErbB2 Therapy

The HER2/ErbB2 monoclonal antibody (mAb) trastuzumab is combined with chemotherapy as a standard-of-care for newly diagnosed HER2+ breast cancer patients, but some patients treated with this combination therapy experience early relapse. Our analysis of data from a clinical trial evaluating the efficacy of chemotherapy plus/minus trastuzumab suggested that the magnitude of trastuzumab benefit on distant disease-free survival was higher for increasing expression of the IL21 receptor (IL21R). Therefore, we investigated a possible role for IL21 signaling in promoting HER2 mAb therapeutic efficacy. We found that IL21R-deficient mice and wild-type mice treated with a neutralizing anti-IL21 mAb were less susceptible to trastuzumab-like anti-ErbB2 therapy. Furthermore, IL21R expression on CD8+ T cells, but not on natural killer cells, was required for optimal anti-ErbB2 mAb efficacy, and IL21 expression was enhanced in tumor-infiltrating CD4+ T lymphocytes after anti-ErbB2 therapy. Finally, we found that administering recombinant IL21 in combination with anti-ErbB2 therapy was therapeutic against primary tumors and experimental metastases in mice. Collectively, our findings suggest that elevating IL21 signaling may enhance trastuzumab efficacy, thus constituting a novel candidate strategy to overcome trastuzumab resistance and improve patient survival. Cancer Res; 76(2); 264–74. ©2016 AACR.

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KIR and HLA in Skin Cancer

Natural killer (NK)–cell phenotype is partially mediated through binding of killer-cell immunoglobulin-like receptors (KIR) with HLA class I ligands. The KIR gene family is highly polymorphic and not well captured by standard genome-wide association study approaches. Here, we tested the hypothesis that variations in KIR gene content combined with HLA class I ligand status is associated with keratinocyte skin cancers using a population-based study of basal cell carcinoma (BCC) and squamous cell carcinomas (SCC). We conducted an interaction analysis of KIR gene content variation and HLA-B (Bw4 vs. Bw6) and HLA-C (C1 vs. C2). KIR centromeric B haplotype was associated with significant risk of multiple BCC tumors (OR, 2.39; 95% confidence interval, 1.10–5.21), and there was a significant interaction between HLA-C and the activating gene KIR2DS3 for BCC (Pinteraction = 0.005). Furthermore, there was significant interaction between HLA-B and telomeric KIR B haplotype (containing the activating genes KIR3DS1 and KIR2DS1) as well as HLA-B and the activating KIR gene KIR2DS5 (Pinteraction 0.001 and 0.012, respectively). Similar but greatly attenuated associations were observed for SCC. Moreover, previous in vitro models demonstrated that p53 is required for upregulation of NK ligands, and accordingly, we observed there was a strong association between the KIR B haplotype and p53 alteration in BCC tumors, with a higher likelihood that KIR B carriers harbor abnormal p53 (P < 0.004). Taken together, our data suggest that functional interactions between KIR and HLA modify risks of BCC and SCC and that KIR encoded by the B genes provides selective pressure for altered p53 in BCC tumors. Cancer Res; 76(2); 370–6. ©2016 AACR.

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PRC2, Th1 Chemokines, and Tumor Immunity

Infiltration of tumors with effector T cells is positively associated with therapeutic efficacy and patient survival. However, the mechanisms underlying effector T-cell trafficking to the tumor microenvironment remain poorly understood in patients with colon cancer. The polycomb repressive complex 2 (PRC2) is involved in cancer progression, but the regulation of tumor immunity by epigenetic mechanisms has yet to be investigated. In this study, we examined the relationship between the repressive PRC2 machinery and effector T-cell trafficking. We found that PRC2 components and demethylase JMJD3-mediated histone H3 lysine 27 trimethylation (H3K27me3) repress the expression and subsequent production of Th1-type chemokines CXCL9 and CXCL10, mediators of effector T-cell trafficking. Moreover, the expression levels of PRC2 components, including EZH2, SUZ12, and EED, were inversely associated with those of CD4, CD8, and Th1-type chemokines in human colon cancer tissue, and this expression pattern was significantly associated with patient survival. Collectively, our findings reveal that PRC2-mediated epigenetic silencing is not only a crucial oncogenic mechanism, but also a key circuit controlling tumor immunosuppression. Therefore, targeting epigenetic programs may have significant implications for improving the efficacy of current cancer immunotherapies relying on effective T-cell–mediated immunity at the tumor site. Cancer Res; 76(2); 275–82. ©2015 AACR.

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PD-1-Mediated Paralysis of DCs

The PD-1:PD-L1 immune signaling axis mediates suppression of T-cell–dependent tumor immunity. PD-1 expression was recently found to be upregulated on tumor-infiltrating murine (CD11c+CD11b+CD8−CD209a+) and human (CD1c+CD19−) myeloid dendritic cells (TIDC), an innate immune cell type also implicated in immune escape. However, there is little knowledge concerning how PD-1 regulates innate immune cells. In this study, we examined the role of PD-1 in TIDCs derived from mice bearing ovarian tumors. Similar to lymphocytes, TIDC expression of PD-1 was associated with expression of the adapter protein SHP-2, which signals to NF-κB; however, in contrast to its role in lymphocytes, we found that expression of PD-1 in TIDC tonically paralyzed NF-κB activation. Further mechanistic investigations showed that PD-1 blocked NF-κB–dependent cytokine release in a SHP-2–dependent manner. Conversely, inhibition of NF-κB–mediated antigen presentation by PD-1 occurred independently of SHP-2. Collectively, our findings revealed that PD-1 acts in a distinct manner in innate immune cells compared with adaptive immune cells, prompting further investigations of the signaling pathways controlled by this central mediator of immune escape in cancer. Cancer Res; 76(2); 239–50. ©2015 AACR.

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MYC and Pten Cooperate to Induce Prostate Cancer

Genetic instability, a hallmark feature of human cancers including prostatic adenocarcinomas, is considered a driver of metastasis. Somatic copy number alterations (CNA) are found in most aggressive primary human prostate cancers, and the overall number of such changes is increased in metastases. Chromosome 10q23 deletions, encompassing PTEN, and amplification of 8q24, harboring MYC, are frequently observed, and the presence of both together portends a high risk of prostate cancer-specific mortality. In extant genetically engineered mouse prostate cancer models (GEMM), isolated MYC overexpression or targeted Pten loss can each produce early prostate adenocarcinomas, but are not sufficient to induce genetic instability or metastases with high penetrance. Although a previous study showed that combining Pten loss with focal MYC overexpression in a small fraction of prostatic epithelial cells exhibits cooperativity in GEMMs, additional targeted Tp53 disruption was required for formation of metastases. We hypothesized that driving combined MYC overexpression and Pten loss using recently characterized Hoxb13 transcriptional control elements that are active in prostate luminal epithelial cells would induce the development of genomic instability and aggressive disease with metastatic potential. Neoplastic lesions that developed with either MYC activation alone (Hoxb13-MYC) or Pten loss alone (Hoxb13-Cre∣PtenFl/Fl) failed to progress beyond prostatic intraepithelial neoplasia and did not harbor genomic CNAs. By contrast, mice with both alterations (Hoxb13-MYC∣Hoxb13-Cre∣PtenFl/Fl, hereafter, BMPC mice) developed lethal adenocarcinoma with distant metastases and widespread genome CNAs that were independent of forced disruption of Tp53 and telomere shortening. BMPC cancers lacked neuroendocrine or sarcomatoid differentiation, features uncommon in human disease but common in other models of prostate cancer that metastasize. These data show that combined MYC activation and Pten loss driven by the Hoxb13 regulatory locus synergize to induce genomic instability and aggressive prostate cancer that phenocopies the human disease at the histologic and genomic levels. Cancer Res; 76(2); 283–92. ©2015 AACR.

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Guanylin Suppression by Calorie-Induced ER Stress in Obesity

Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks of malignancy remains unclear. During colon cancer development in humans or animals, attenuation of the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs due to loss of its paracrine hormone ligand guanylin contributes universally to malignant progression. In this study, we explored a link between obesity and GUCY2C silencing in colorectal cancer. Using genetically engineered mice on different diets, we found that diet-induced obesity caused a loss of guanylin expression in the colon with subsequent GUCY2C silencing, epithelial dysfunction, and tumorigenesis. Mechanistic investigations revealed that obesity reversibly silenced guanylin expression through calorie-dependent induction of endoplasmic reticulum stress and the unfolded protein response in intestinal epithelial cells. In transgenic mice, enforcing specific expression of guanylin in intestinal epithelial cells restored GUCY2C signaling, eliminating intestinal tumors associated with a high calorie diet. Our findings show how caloric suppression of the guanylin–GUCY2C signaling axis links obesity to negation of a universal tumor suppressor pathway in colorectal cancer, suggesting an opportunity to prevent colorectal cancer in obese patients through hormone replacement with the FDA-approved oral GUCY2C ligand linaclotide. Cancer Res; 76(2); 339–46. ©2016 AACR.

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HBXIP and LSD1 Scaffolded by Hotair Activate c-Myc

c-Myc is regarded as a transcription factor, but the basis for its function remains unclear. Here, we define a long noncoding RNA (lncRNA)/protein complex that mediates the transcriptional activation by c-Myc in breast cancer cells. Among 388 c-Myc target genes in human MCF-7 breast cancer cells, we found that their promoters could be occupied by the oncoprotein HBXIP. We confirmed that the HBXIP expression correlated with expression of the c-Myc target genes cyclin A, eIF4E, and LDHA. RNAi-mediated silencing of HBXIP abolished c-Myc–mediated upregulation of these target genes. Mechanistically, HBXIP interacted directly with c-Myc through the leucine zippers and recruited the lncRNA Hotair along with the histone demethylase LSD1, for which Hotair serves as a scaffold. Silencing of HBXIP, Hotair, or LSD1 was sufficient to block c-Myc–enhanced cancer cell growth in vitro and in vivo. Taken together, our results support a model in which the HBXIP/Hotair/LSD1 complex serves as a critical effector of c-Myc in activating transcription of its target genes, illuminating long-standing questions on how c-Myc drives carcinogenesis. Cancer Res; 76(2); 293–304. ©2015 AACR.

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Simultaneous detection of circulating immunological parameters and tumor biomarkers in early stage breast cancer patients during adjuvant chemotherapy

Abstract

Background

Chemotherapy-induced immune suppression has mainly been studied in patients with advanced cancer, but the influence of chemotherapy on the immune system in early stage cancer patients has so far not been studied systematically. The aim of the present study was to monitor the immune system during anthracycline- and taxane-based adjuvant chemotherapy in early stage breast cancer patients, to assess the impact of circulating tumor cells on selected immune parameters and to reveal putative angiogenic effects of circulating endothelial cells.

Methods

Peripheral blood samples from 20 early stage breast cancer patients were analyzed using a flow cytometric multi-color of antibodies to enumerate lymphocyte and dendritic cell subsets, as well as endothelial and tumor cells. An enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of various serological factors.

Results

During chemotherapy, all immunological parameters and angiogenesis surrogate biomarkers showed significant decreases. The numbers of circulating tumor cells showed significant inverse correlations with the numbers of T helper cells, a lymphocyte subset directly related to effective anti-tumor responses. Reduced T helper cell numbers may contribute to systemic immunosuppression and, as such, the activation of dormant tumor cells.

Conclusions

From our results we conclude that adjuvant chemotherapy suppresses immune function in early stage breast cancer patients. In addition, we conclude that the presence of circulating tumor cells, defined as pan-cytokeratin⁺, CD326⁺, CD45⁻ cells, may serve as an important indicator of a patient's immune status. Further investigations are needed to firmly define circulating tumor cells as a predictor for the success of breast cancer adjuvant chemotherapy.

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Imaging heterogeneity of peptide delivery and binding in solid tumors using SPECT imaging and MRI

Abstract

Background

As model system, a solid-tumor patient-derived xenograft (PDX) model characterized by high peptide receptor expression and histological tissue homogeneity was used to study radiopeptide targeting. In this solid-tumor model, high tumor uptake of targeting peptides was expected. However, in vivo SPECT images showed substantial heterogeneous radioactivity accumulation despite homogenous receptor distribution in the tumor xenografts as assessed by in vitro autoradiography. We hypothesized that delivery of peptide to the tumor cells is dictated by adequate local tumor perfusion. To study this relationship, sequential SPECT/CT and MRI were performed to assess the role of vascular functionality in radiopeptide accumulation.

Methods

High-resolution SPECT and dynamic contrast-enhanced (DCE)-MRI were acquired in six mice bearing PC295 PDX tumors expressing the gastrin-releasing peptide (GRP) receptor. Two hours prior to SPECT imaging, animals received 25 MBq ¹¹¹In(DOTA-(βAla)2-JMV594) (25 pmol). Images were acquired using multipinhole SPECT/CT. Directly after SPECT imaging, MR images were acquired on a 7.0-T dedicated animal scanner. DCE-MR images were quantified using semi-quantitative and quantitative models. The DCE-MR and SPECT images were spatially aligned to compute the correlations between radioactivity and DCE-MRI-derived parameters over the tumor.

Results

Whereas histology, in vitro autoradiography, and multiple-weighted MRI scans all showed homogenous tissue characteristics, both SPECT and DCE-MRI showed heterogeneous distribution patterns throughout the tumor. The average Spearman's correlation coefficient between SPECT and DCE-MRI ranged from 0.57 to 0.63 for the "exchange-related" DCE-MRI perfusion parameters.

Conclusions

A positive correlation was shown between exchange-related DCE-MRI perfusion parameters and the amount of radioactivity accumulated as measured by SPECT, demonstrating that vascular function was an important aspect of radiopeptide distribution in solid tumors. The combined use of SPECT and MRI added crucial information on the perfusion efficiency versus radiopeptide uptake in solid tumors and showed that functional tumor characteristics varied locally even when the tissue appeared homogenous on current standard assessment techniques.

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Multimorbidity, cognitive function, and physical activity

Abstract

Previous research demonstrates that both physical activity and multimorbidity are associated with cognitive function. However, the extent to which physical activity may moderate the relationship between multimorbidity and cognitive function has not been thoroughly evaluated. Data from the 1999–2002 NHANES were used (60+ years; N = 2157). A multimorbidity index variable was created based on physician diagnosis of a multitude of chronic diseases. Physical activity was self-reported and cognitive function was evaluated from the digit symbol substitution test. Multimorbidity was inversely associated with cognitive function for the unadjusted and adjusted models. However, generally, multimorbidity was no longer associated with cognitive function for the majority of older adults who achieved the minimum recommended physical activity level (≥2000 MET-min-month), as issued by the United States Department of Health and Human Services. In this national sample of older adults, there was some evidence to suggest that physical activity moderates the relationship between multimorbidity and cognitive function.

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The relationship of nitric oxide synthesis capacity, oxidative stress, and albumin-to-creatinine ratio in black and white men: the SABPA study

Abstract

Inadequate substrate availability and increased nitric oxide synthase inhibitor levels attenuate nitric oxide (NO) synthesis, whereas increased vascular oxidative stress may lead to inactivation of NO. We compared markers of NO synthesis capacity and oxidative stress in a bi-ethnic male population. Inter-relationships of ambulatory blood pressure and urinary albumin-to-creatinine ratio with NO synthesis capacity and oxidative stress markers were investigated. NO synthesis capacity markers (L-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA)) and oxidative stress markers (serum peroxides, total glutathione, glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), and catalase) were measured. Black men displayed higher blood pressure and albumin-to-creatinine ratio (all p < 0.001), while NO synthesis capacity was more favorable (higher L-arginine and lower ADMA (p ≤ 0.003)). Antioxidant enzyme activities were similar except for the redox status markers (GR activity and GR/GPx ratio), which were upregulated in black men (p < 0.001). In black men, ADMA was inversely related to GPx activity (R ² = 0.15; β = −0.20; p = 0.050) and GPx/SOD ratio (R ² = 0.24; β = −0.37; p < 0.001), but none of these markers related to blood pressure or albumin-to-creatinine ratio. In white men, albumin-to-creatinine ratio was positively associated with ADMA (R ² = 0.18; β = 0.39; p < 0.001) while ADMA was inversely related to GR activity (R ² = 0.26; β = −0.29; p = 0.002) and GR/GPx ratio (R ² = 0.25; β = −0.28; p = 0.003). Black men with elevated blood pressure and albumin-to-creatinine ratio displayed a favorable NO synthesis capacity. This may be counteracted by increased inactivation of NO, although it was not linked to vascular or renal phenotypes. In white men, reduced NO synthesis capacity may lower NO bio-availability, thereby influencing the albumin-to-creatinine ratio.

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Pancreatic Cystic Mass

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Radiation-Induced Dedifferentiation of Head and Neck Cancer Cells into Cancer Stem Cells Depends on HPV status

Publication date: Available online 14 January 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Erina Vlashi, Allen M. Chen, Sabrina Boyrie, Garrett Yu, Andrea Nguyen, Philip A. Brower, Clayton B. Hess, Frank Pajonk
PurposeHuman papilloma virus (HPV), HPV-16, is one of the most important prognostic factors for patients with head and neck squamous cell carcinomas (HNSCCs). HPV-positive HNSCCs have a favorable response to radiation therapy (RT) and superior overall survival (OS) compared to HPV-negative HNSCCs. However, an explanation for the mechanisms responsible for the inherent radiosensitivity of HPV-positive HNSCC remains elusive.Methods and MaterialsRecords of a cohort of 162 HNSCC patients were reviewed and their outcomes were correlated with their HPV status. Using a panel of HPV-positive and HPV-negative HNSCC cell lines expressing a reporter for cancer stem cells (CSCs) we characterized HPV-positive and HPV-negative lines via flow cytometry, sphereforming capacity assays in vitro, and limiting dilution assays in vivo. Non-CSCs were treated with different doses of radiation and the dedifferentiation of non-CSCs into CSCs was investigated via flow cytometry and qRT-PCR for re-expression of reprogramming factors.ResultsPatients with HPV-positive tumors have superior OS and local-regional control. HPV-positive HNSCC cell lines have lower numbers of CSCs, which inversely correlates with radiosensitivity. HPV-negative HNSCC cell lines lack hierarchy due to enhanced spontaneous dedifferentiation. Non-CSCs from HPV-negative lines show enhanced radiation-induced dedifferentiation compared to HPV-positive lines, and RT induced re-expression of Yamanaka reprogramming factors.ConclusionsSupporting the favorable prognosis of HPV-positive HNSCCs, we show that HPV-positive HNSCCs have (1) a lower frequency of CSCs, (2) RT can dedifferentiate HNSCC cells into CSCs, and (3) radiation-induced dedifferentiation depends on the HPV status of the tumor.

Teaser

Our studies provide another layer of scientific evidence that offers an alternative explanation for the improved long-term outcome of HPV-positive HNSCC patients: lower frequency of intrinsic CSCs, and an impaired ability to dedifferentiate into HNSCC stem cells after radiation therapy. Thus, preventing spontaneous and radiation-induced dedifferentiation events from occurring could potentially result in significantly improved loco-regional control for these patients.


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Survival impact of adjuvant radiotherapy in Masaoka stage II-IV thymomas – A systematic review and meta-analysis

Publication date: Available online 14 January 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Yu Jin Lim, Eunji Kim, Hak Jae Kim, Hong-Gyun Wu, Jinchun Yan, Qin Liu, Shilpen Patel
PurposeDue to the lack of randomized evidence, no conclusion has been made concerning the role of postoperative radiotherapy (PORT) in thymomas. This systematic review and meta-analysis evaluated the survival impact of PORT in stage II-IV thymomas.Methods and MaterialsA database search was conducted with EMBASE, PubMed, Web of Science, Cochrane Library, and Ovid from inception to August 2015. Thymic carcinomas were excluded, and studies comparing overall survival (OS) with and without PORT in thymomas were included. The hazard ratios (HRs) of OS were extracted, and a random-effects model was used in the pooled analysis.ResultsSeven retrospective series with a total of 1,724 patients were included and analyzed. Almost all of the patients underwent macroscopically complete resection, and thymoma histology was confirmed by the World Health Organization criteria. In the overall analysis of stage II-IV thymomas, OS was not altered with the receipt of PORT (HR 0.79, 95% confidence interval [CI] 0.58‒1.08). Although PORT was not associated with survival difference in Masaoka stage II disease (HR 1.45, 95% CI 0.83‒2.55), improved OS was observed with the addition of PORT in the discrete pooled analysis of stage III-IV (HR 0.63, 95% CI 0.40‒0.99). Significant heterogeneity and publication bias were not found in the analyses.ConclusionsFrom the present meta-analysis of the sole primary thymomas, we suggest the potential OS benefit of PORT in locally advanced tumors with macroscopically complete resection, but not in stage II disease. Further investigations with sufficient survival data are needed to establish detailed treatment indications.

Teaser

This study showed survival impact of postoperative radiotherapy (PORT) in thymomas based on the pooled analyses of time-to-event overall survival data of existing observational studies. Although there was no significant difference with and without PORT in Masaoka stage II, improved survival was observed in stage III-IV thymomas. We could suggest clinical benefit of PORT in the locally advanced tumors. Further large-scale analyses are needed to verify the present results.


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Oncology E-Learning for Undergraduate. A Prospective Randomized Controlled Trial

Abstract

The e-learning education is a promising method, but there are few prospective randomized publications in oncology. The purpose of this study was to assess the level of retention of information in oncology from undergraduate students of physiotherapy. A prospective, controlled, randomized, crossover study, 72 undergraduate students of physiotherapy, from the second to fourth years, were randomized to perform a course of physiotherapy in oncology (PHO) using traditional classroom or e-learning. Students were offered the same content of the subject. The teacher in the traditional classroom model and the e-learning students used the Articulate® software. The course tackled the main issues related to PHO, and it was divided into six modules, 18 lessons, evaluated by 126 questions. A diagnosis evaluation was performed previous to the course and after every module. The sample consisted of 67 students, allocated in groups A (n = 35) and B (n = 32), and the distribution was homogeneous between the groups. Evaluating the correct answers, we observed a limited score in the pre-test (average grade 44.6 %), which has significant (p < 0.001) improvement in post-test evaluation (average grade 73.9 %). The correct pre-test (p = 0.556) and post-test (p = 0.729) evaluation and the retention of information (p = 0.408) were not different between the two groups. The course in PHO allowed significant acquisition of knowledge to undergraduate students, but the level of information retention was statistically similar between the traditional classroom form and the e-learning, a fact that encourages the use of e-learning in oncology.

Clinical Trial Registration number

REBECU1111-1142-1963

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Ovarian cancer in Lynch syndrome; a systematic review

Publication date: March 2016
Source:European Journal of Cancer, Volume 55
Author(s): J.M. Helder-Woolderink, E.A. Blok, H.F.A. Vasen, H. Hollema, M.J. Mourits, G.H. De Bock
ObjectiveThe aim was to systematically review the characteristics of ovarian cancer in women with Lynch syndrome (LS) and evaluate the role of surveillance in detection of ovarian cancer in LS.MethodsAll studies between 1979 and 2015 of women with ovarian cancer and LS or at 50% risk of LS were evaluated. Two reviewers independently evaluated eligible studies and extracted data on age at diagnosis, histological type, FIGO stage, and way of detection according to pre-specified criteria. The studies were assessed for quality using the Newcastle-Ottawa quality assessment scales.ResultsThe quality score of the 49 identified studies was at least 6 out of 8 and provide clinical information on 747 LS women with ovarian cancer. The mean age at diagnosis was 45.3 (range 19–82) years. Most frequent mutations were MSH2 (47%) and MLH1 (38%). Histopathological data were available for 445 women. The most frequently reported histological type was mixed type (mucinous/endometrioid/clear cell carcinomas) (n = 136; 31%). Most tumours (281, 65%) were diagnosed at an early stage (FIGO I/II). Six studies evaluating the effect of surveillance of ovarian cancer, reported that seven of 22 (32%) ovarian cancers were found during surveillance, 6/7 (86%) were detected at an early stage.ConclusionThis systematic review describes that ovarian cancer in women with LS has a wide age-range of onset, is often diagnosed at an early stage with frequently endometrioid/clear cell histology. Data about the role of surveillance in detection of ovarian cancer in women with LS are scarce however detection at an early stage seems possible.



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Ultrasound surveillance for radiation-induced thyroid carcinoma in adult survivors of childhood cancer

Publication date: March 2016
Source:European Journal of Cancer, Volume 55
Author(s): Enrico Brignardello, Francesco Felicetti, Anna Castiglione, Marco Gallo, Francesca Maletta, Giuseppe Isolato, Eleonora Biasin, Franca Fagioli, Andrea Corrias, Nicola Palestini
IntroductionThe optimal surveillance strategy to screen for thyroid carcinoma childhood cancer survivors (CCS) at increased risk is still debated. In our clinical practice, beside neck palpation we routinely perform thyroid ultrasound (US). Here we describe the results obtained using this approach.MethodsWe considered all CCS referred to our long term clinic from November 2001 to September 2014. One hundred and ninety-seven patients who had received radiation therapy involving the thyroid gland underwent US surveillance. Thyroid US started 5 years after radiotherapy and repeated every 3 years, if negative.ResultsAmong 197 CCS previously irradiated to the thyroid gland, 74 patients (37.5%) developed thyroid nodules, and fine-needle aspiration was performed in 35. In 11 patients the cytological examination was suspicious or diagnostic for malignancy (TIR 4/5), whereas a follicular lesion was diagnosed in nine. Patients with TIR 4/5 cytology were operated and in all cases thyroid cancer diagnosis was confirmed. The nine patients with TIR 3 cytology also underwent surgery and a carcinoma was diagnosed in three of them. Prevalence of thyroid cancer was 7.1%. Tumour size ranged between 4 and 25 mm, but six (43%) were classified T3 because of extra-thyroidal extension. Six patients had nodal metastases; in eight patients the tumour was multifocal. At the time of the study all patients are disease free, without evidence of surgery complications.ConclusionApplying our US surveillance protocol, the prevalence of radiation-induced thyroid cancer is high. Histological features of the thyroid cancers diagnosed in our cohort suggest that most of them were clinically relevant tumours.



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Simotinib as a modulator of P-glycoprotein: substrate, inhibitor, or inducer?.

As a new antitumor drug, simotinib hydrochloride is prescribed for prolonged periods, often to patients with comorbidities. Therefore, the risk for developing drug resistance and drug-drug interactions between simotinib and other agents has to be taken into consideration. As P-glycoprotein (P-gp) is an efflux transporter, which plays a significant role in drug resistance and influences the pharmacological properties and toxicities of the drugs it interacts with, the interactions between simotinib and P-gp were investigated. Cytotoxicity was measured using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Intracellular drug concentrations were detected by high-performance liquid chromatography, fluorescence-activated cell sorting and using a fluorescence reader. P-gp ATPase activity was measured using the Pgp-Glo assay, and intracellular pH was assessed using the fluorescent probe 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl. The expression and transcription of P-gp were detected by western blotting and the luciferase assay. Simotinib has no cross-resistance to P-gp substrates, and its efflux rate was independent of either the P-gp expression or the coadministered P-gp substrate. Simotinib reversed chemotherapeutic agent resistance in a short time by increasing the intracellular concentration of the chemotherapeutic agent and blocked rhodamine 123 efflux. Further studies demonstrated that simotinib inhibited P-gp activity by modulating its ATPase activity and the intracellular pH. Although simotinib induced P-gp expression after extended treatment, the induced expression of P-gp had little impact on drug resistance. Simotinib is not a substrate of P-gp. As a modulator, it functions mainly as an inhibitor of P-gp by modulating the intracellular pH and ATPase activity, although it also induces P-gp expression after extended treatment. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Impact of Body Weight and Body Composition on Ovarian Cancer Prognosis

Abstract

Measures of body weight and anthropometrics such as body mass index (BMI) are commonly used to assess nutritional status in clinical conditions including cancer. Extensive research has evaluated associations between body weight and prognosis in ovarian cancer patients, yet little is known about the potential impact of body composition (fat mass (FM) and fat-free mass (FFM)) in these patients. Thus, the purpose of this publication was to review the literature (using PubMed and EMBASE) evaluating the impact of body weight and particularly body composition on surgical complications, morbidity, chemotherapy dosing and toxicity (as predictors of prognosis), and survival in ovarian cancer patients. Body weight is rarely associated with intra-operative complications, but obesity predicts higher rates of venous thromboembolism and wound complications post-operatively in ovarian cancer patients. Low levels of FM and FFM are superior predictors of length of hospital stay compared to measures of body weight alone, but the role of body composition on other surgical morbidities is unknown. Obesity complicates chemotherapy dosing due to altered pharmacokinetics, imprecise dosing strategies, and wide variability in FM and FFM. Measurement of body composition has the potential to reduce toxicity if the results are incorporated into chemotherapy dosing calculations. Some findings suggest that excess body weight adversely affects survival, while others find no such association. Limited studies indicate that FM is a better predictor of survival than body weight in ovarian cancer patients, but the direction of this relationship has not been determined. In conclusion, body composition as an indicator of nutritional status is a better prognostic tool than body weight or BMI alone in ovarian cancer patients.

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Post-progression survival in patients with advanced hepatocellular carcinoma resistant to sorafenib

Summary

Background Since the approval of sorafenib, no other agent has been proven to show survival benefits in clinical trials involving patients with advanced hepatocellular carcinoma (HCC) resistant to sorafenib. Prognostic factors for survival after tumor progression in sorafenib-treated patients are critical for designing second-line trials. Methods To determine the factors affecting the post-progression survival (PPS) after sorafenib treatment, additional analyses were conducted using fixed data obtained from our previous prospective study. Data on patients with advanced HCC treated with sorafenib were analyzed in view of patient characteristics at the time of tumor progression and the progression pattern (intra−/extrahepatic growth or emergence of new intra−/extrahepatic lesions). Results Of the 89 enrolled patients, 70 were diagnosed with disease progression according to the Response Evaluation Criteria in Solid Tumors version 1.1. Multivariate Cox's regression analysis revealed that Child–Pugh scores of ≥7, macrovascular invasion (MVI), and alpha-fetoprotein of >400 ng/mL were independent predictors of poor PPS. Although both extrahepatic metastasis (EHM) and MVI were characteristics of advanced HCC, EHM was not determined as a prognostic factor. Additionally, the emergence of new extrahepatic lesions also served as an independent indicator of a poor prognosis. The PPS of the patients was well stratified according to the index based on the sum of these prognostic factors, ranging from 0 to 4. Conclusions Child–Pugh score of ≥7, AFP of >400 ng/mL, MVI, and new extrahepatic lesions at the time of progression may be utilized to assess the prognosis and taken into consideration when designing second-line trials.

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Pharmacokinetics, metabolism, and excretion of 14 C-labeled belinostat in patients with recurrent or progressive malignancies

Summary

Background Belinostat, a potent pan-inhibitor of histone deacetylase (HDAC) enzymes, is approved in the United States (US) for relapsed/refractory peripheral T-cell lymphoma. In nonclinical studies, bile and feces were identified as the predominant elimination routes (50–70 %), with renal excretion accounting for ~30–50 %. A Phase 1 human mass balance study was conducted to identify species-dependent variations in belinostat metabolism and elimination. Methods Patients received a single 30-min intravenous (IV) infusion of ¹⁴C-labeled belinostat (1500 mg). Venous blood samples and pooled urine and fecal samples were evaluated using liquid chromatography - tandem mass spectroscopy for belinostat and metabolite concentrations pre-infusion through 7 days post-infusion. Total radioactivity was determined using liquid scintillation counting. Continued treatment with nonradiolabled belinostat (1000 mg/m² on Days 1–5 every 21 days) was permitted. Results Belinostat was extensively metabolized and mostly cleared from plasma within 8 h (N = 6), indicating that metabolism is the primary route of elimination. Systemic exposure for the 5 major metabolites was >20 % of parent, with belinostat glucuronide the predominant metabolite. Mean recovery of radioactive belinostat was 94.5 % ± 4.0 %, with the majority excreted within 48 and 96 h in urine and feces, respectively. Renal elimination was the principal excretion route (mean 84.8 % ± 9.8 % of total dose); fecal excretion accounted for 9.7 % ± 6.5 %. Belinostat was well tolerated, with mostly mild to moderate adverse events and no treatment-related severe/serious events. Conclusion Mass balance was achieved (~95 % mean recovery), with metabolism identified as the primary route of elimination. Radioactivity was predominantly excreted renally as belinostat metabolites.

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Association of DNA repair and xenobiotic pathway gene polymorphisms with genetic susceptibility to gastric cancer patients in West Bengal, India

Abstract

Gastric cancer is one of the most common malignancies in India. DNA repair gene or xenobiotic pathway gene polymorphisms have recently been shown to affect individual susceptibility to gastric cancer. Here, the possible interaction between common polymorphisms in X-ray repair cross complementing group I (XRCC1) gene and glutathione S-transferase (GST) genes (GSTM1, GSTT1 and GSTP1), smoking and alcohol consumption and overall survival in gastric cancer patients were evaluated. In this population-based case control study, 70 gastric cancer patients and 82 healthy controls were enrolled. The epidemiological data were collected by a standard questionnaire, and blood samples were collected from each individual. XRCC1 Arg194Trp, Arg280His and Arg399Gln polymorphisms were determined by polymerase chain reaction and direct DNA sequencing. GSTM1 and GSTT1 null polymorphisms and GSTP1 Ile105Val polymorphism were identified by multiplex polymerase chain reaction and restriction fragment length polymorphism (RFLP), respectively. The risk of gastric cancer was significantly elevated in individuals with XRCC1 Arg/Gln +Gln/Gln (p = 0.031; odds ratio = 2.32; 95 % confidence interval (CI) 1.07–5.06) and GSTP1 Val/Val genotype (p = 0.009; odds ratio = 8.64; 95 % CI 1.84–40.55). An elevated risk for GC was observed in smokers and alcohol consumers carrying GSTP1 Ile/Val +Val/Val genotype (p = 0.041; odds ratio = 3.71; 95 % CI 0.98–14.12; p = 0.002; odds ratio = 12.31; 95 % CI 1.71–88.59). These findings suggest that XRCC1 rs25487 and GSTP1 rs1695 can be considered as a risk factor associated with gastric cancer and might be used as a molecular marker for evaluating the susceptibility of the disease.

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Evaluation of 188 Re-labeled NGR–VEGI protein for radioimaging and radiotherapy in mice bearing human fibrosarcoma HT-1080 xenografts

Abstract

Vascular endothelial growth inhibitor (VEGI) is an anti-angiogenic protein, which includes three isoforms: VEGI-174, VEGI-192, and VEGI-251. The NGR (asparagine–glycine–arginine)-containing peptides can specifically bind to CD13 (Aminopeptidase N) receptor which is overexpressed in angiogenic blood vessels and tumor cells. In this study, a novel NGR–VEGI fusion protein was prepared and labeled with ¹⁸⁸Re for radioimaging and radiotherapy in mice bearing human fibrosarcoma HT-1080 xenografts. Single photon emission computerized tomography (SPECT) imaging results revealed that ¹⁸⁸Re-NGR–VEGI exhibits good tumor-to-background contrast in CD13-positive HT-1080 tumor xenografts. The CD13 specificity of ¹⁸⁸Re-NGR–VEGI was further verified by significant reduction of tumor uptake in HT-1080 tumor xenografts with co-injection of the non-radiolabeled NGR–VEGI protein. The biodistribution results demonstrated good tumor-to-muscle ratio (4.98 ± 0.25) of ¹⁸⁸Re-NGR–VEGI at 24 h, which is consistent with the results from SPECT imaging. For radiotherapy, 18.5 MBq of ¹⁸⁸Re-NGR–VEGI showed excellent tumor inhibition effect in HT-1080 tumor xenografts with no observable toxicity, which was confirmed by the tumor size change and hematoxylin and eosin (H&E) staining of major mouse organs. In conclusion, these data demonstrated that ¹⁸⁸Re-NGR–VEGI has the potential as a theranostic agent for CD13-targeted tumor imaging and therapy.

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MicroRNA-503 represses epithelial–mesenchymal transition and inhibits metastasis of osteosarcoma by targeting c-myb

Abstract

Deregulated expression of miRNAs contributes to the development of osteosarcoma. Our previous study has showed that miR-503 was downregulated in osteosarcoma tissues. However, the mechanism of the miR-503 in osteosarcoma development still remains largely undefined. In our study, we found that miR-503 overexpression suppressed cell invasion and migration and inhibited epithelial-to-mesenchymal transition (EMT) of MG-63. Furthermore, we identified that c-myb, an oncogene, was a direct target of miR-503. Moreover, overexpression of c-myb could rescue miR-503-suppressed invasion and EMT. The expression of c-myb was upregulated in osteosarcoma cell lines. Therefore, we conclude that high miR-503 expression suppressed osteosarcoma cell mobility and EMT through targeting c-myb, and this may serve as a therapeutic target.

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Caveolin-1 affects tumor drug resistance in esophageal squamous cell carcinoma by regulating expressions of P-gp and MRP1

Abstract

Esophageal squamous cell carcinoma (ESCC) is the most common cancer in China, and multidrug resistance (MDR) remains one of the biggest problems in ESCC chemotherapy. In this study, we aimed to investigate the mechanism of Caveolin-1, an integral membrane protein, on regulating ESCC MDR. First, immunohistochemistry was used to check the protein expression of Caveolin-1, MDR-related protein of P-glycoprotein (P-gp), and multidrug resistance protein 1 (MRP1) in 84 pathologically characterized ESCC tissues, matched adjacent tumor, and adjacent normal-looking tissues. The results showed that Caveolin-1 expression level was elevated in ESCC tissues than that of matched adjacent tumor and adjacent normal-looking tissues (P < 0.05), and the expression of Caveolin-1 has close correlation with P-gp and MRP1 during tumor genesis of ESCC (P = 0.034, P = 0.009, respectively). Then, Caveolin-1 overexpression and knockdown were used to investigate its effect on expressions of P-gp and MRP1 in ESCC cell line Ec9706. The messenger RNA (mRNA) and protein expression levels of P-gp and MRP1 were checked by real-time quantitative reverse transcription-PCR (qRT-PCR) and Western blot (WB). The results showed that Caveolin-1 overexpression significantly promotes the mRNA and protein expression of MRP1 (P < 0.05), while almost has no effect on the mRNA and protein expression of P-gp (P > 0.05); Cavoelin-1 knockdown inhibits the mRNA and protein expressions of both P-gp and MRP1 (P < 0.05). The similar result was found in another ESCC cell line Eca109. So, it is concluded that Caveolin-1 affects ESCC MDR by regulating the expressions of P-gp and MRP1; therefore, it can be taken as a significant marker and target in tumor therapy.

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The proliferation impairment induced by AQP3 deficiency is the result of glycerol uptake and metabolism inhibition in gastric cancer cells

Abstract

Gastric cancer is a big threat to human health. Effective therapeutic cancer target remains to be discovered. Aquaporin 3 (AQP3) belongs to a family of transmembrane channels that are important in transporting water, glycerol, and other small molecules across the cell membrane. Glycerol that is transported by AQP3 is necessary for cell energy generation and lipid synthesis which fulfill the cell biological processes. Previous studies have shown that AQP3 is implicated in disease progression in several cancer types. However, whether AQP3-regulated glycerol uptake and metabolism were involved in cancer progression remains to be further studied. Our study demonstrated that the expression of AQP3 was positively correlated with glycerol level in human gastric cancer tissues. AQP3 inhibition induced proliferation impairment in gastric cancer cells both in vitro and in vivo. AQP3 inhibition that induced glycerol uptake reduction and glycerol administration would rehabilitate the cell proliferation. The energy and lipid production decreased when AQP3 was knocked down since the cellular glycerol level and several lipogenesis enzymes were downregulated. PI3K/Akt signaling pathway, which was involved in the impaired lipid and ATP production, was also inhibited after AQP3 knockdown. Our study indicated that the energy and lipid production inhibition, which were responsible for gastric cancer cell proliferation impairment, were induced by glycerol uptake reduction after AQP3 knockdown.

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Lin28: an emerging important oncogene connecting several aspects of cancer

Abstract

RNA-binding protein Lin28 was originally found as a heterochronic gene which played a significant role in the development of Caenorhabditis elegans. The tumor suppressor let-7 is a downstream target of Lin28, which has a wide variety of target genes which are involved in many aspects of cellular activities. By inhibition of let-7 and directly binding the target RNAs, Lin28 plays an important role in different biological and pathological processes including differentiation, metabolism, proliferation, pluripotency, and tumorigenesis. Overexpression of Lin28 has been reported in several kinds of cancers and is correlated with poor outcomes. It has been shown that Lin28 could affect the progression of cancers in several ways, such as promoting proliferation, increasing glucose metabolism, and inducing epithelial-mesenchymal transition (EMT) and cancer stem cells. Decrease of Lin28 expression or reactivation of let-7 in cancer cells could induce a reverse effect, indicating their therapeutic values in developing novel strategies for cancer treatment. Here, we will overview the regulatory mechanisms and functions of Lin28 in cancers.

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Increased expression of SOX4 is associated with colorectal cancer progression

Abstract

Sex-determining region Y-related high-mobility group box 4 (SOX4) has been proven to serve as a critical role in cancer progression. However, the pathological role of SOX4 in colorectal cancer (CRC) remains unknown. The aim of this study was to investigate the role of SOX4 in CRC. In this study, we investigated the expression of SOX4 in CRC tissues by immunohistochemistry, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and Western blot. We also evaluated the effect of SOX4 on cell proliferation and invasion by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and transwell assay. The SOX4 messenger RNA (mRNA) and protein expression were markedly higher in CRC tissues compared with adjacent normal mucosa tissues. Inhibition of SOX4 could suppress CRC cell proliferation, and invasion in vitro. Our findings indicate that targeting SOX4 might provide a new therapeutic modality for the treatment of CRC patients.

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ECRG4 as a novel tumor suppressor gene inhibits colorectal cancer cell growth in vitro and in vivo

Abstract

Esophageal cancer related gene 4 (ECRG4) as a tumor suppressor gene inhibits the growth and development of various tumors. Colorectal cancer (CRC), a common malignant tumor in the digestive tract worldwide, is a leading cause of death. The aim of our study was to assess the tumor-suppressing effect of ECRG4 on CRC and explore its related mechanisms in vitro and in vivo. The expression levels of ECRG4 were measured in colorectal cancer tissues and para-carcinoma tissues. ECRG4 gene was transfected into CRC cells to investigate its effect on cell proliferation by MTT, colony formation assay, and cell cycle analysis. Cell apoptosis was assessed by annexin-V/PI, Hoechst 33342 staining, and analysis of apoptosis-related protein expressions in vitro. The in vivo tumorigenesis assays were performed in nude mice. According to the results, there was a lower expression of ECRG4 in CRC tissues compared with normal tissues, which was strongly associated with histology differentiation and lymph node metastasis. Additionally, overexpression of ECRG4 had a significant inhibitory effect on proliferation and promoted apoptosis in Caco-2 and SW480 cells. Moreover, we found that the overexpression of ECRG4 inhibited tumorigenesis in vivo by diminishing the volume and weight of the tumors and inducing apoptosis of tumor cells. Our study indicates that ECRG4 may be a new potential target and prognostic factor for patients with CRC.

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Sprouty4 mediates amphiregulin-induced down-regulation of E-cadherin and cell invasion in human ovarian cancer cells

Abstract

Sprouty (SPRY) proteins are well-characterized factors that inhibit receptor tyrosine kinase (RTK)-mediated activation of cellular signaling pathways. The down-regulation of SPRY4 expression has been reported in human ovarian cancer. However, the specific roles and mechanisms by which SPRY4 affects ovarian cancer progression are completely unknown. Amphiregulin (AREG) binds exclusively to the epidermal growth factor receptor (EGFR) and has been considered to be a dominant autocrine/paracrine EGFR ligand in ovarian cancer. In the present study, we first examined the effects of AREG on SPRY4 expression and the possible underlying molecular mechanisms involved in this process in two human ovarian cancer cell lines. Our results demonstrated that treatment with AREG up-regulated SPRY4 expression by activating the ERK1/2 signaling pathway. In addition, we showed that small interfering RNA (siRNA)-mediated knockdown of SPRY4 attenuated the AREG-induced down-regulation of E-cadherin by inhibiting the expression of SNAIL but not SLUG. In contrast, overexpression of SPRY4 enhanced AREG-induced down-regulation of E-cadherin by increasing the expression of SNAIL. Moreover, SPRY4 knockdown attenuated AREG-induced cell migration and invasion. Overexpression of SPRY4 enhanced AREG-induced cell invasion. This study reveals that SPRY4 is involved in EGFR-mediated human ovarian cancer progression.

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Expression of Pim-3 in colorectal cancer and its relationship with prognosis

Abstract

There is increasing evidence suggesting that the establishment of Pim-3 is involved in tumorigenesis. This study aimed to investigate the expression and clinicopathological significance of Pim-3 in colorectal cancer (CRC). Clinical pathology data were collected from 410 CRC patients who received radical resection and were pathologically confirmed at the Sun Yat-Sen University Cancer Center between October 2002 and December 2008. We compared the expression Pim-3 in the primary focus and liver metastasis and investigated the correlations with other clinical-pathological factors. Multivariate analysis showed that perioperative blood transfusion, local invasion, lymph node and liver metastasis, and Pim-3 expression were independent prognostic factors. The expression of Pim-3 in CRC was higher than that in normal tissues. Patients with positive expression had significant decreases in 5-year survival. Pim-3 expression showed a positive correlation with tumor cell differentiation, local infiltration, and lymph node and liver metastasis. In conclusion, Pim-3 might serve as a novel target and prognosis factor for colorectal cancer.

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MiR-381 inhibits epithelial ovarian cancer malignancy via YY1 suppression

Abstract

Epithelial ovarian cancer (EOC) is a common type of gynecologic cancer, which accounts for the majority of deaths among all gynecologic malignant tumors in developed countries. A series of recent studies suggested that miR-381 might play important roles in the development of various cancer types. However, the biological function of miR-381 in EOC remains to be investigated. We examined the levels of miR-381 expression in EOC tissues and cell lines. We identified miR-381 target genes by bioinformatic prediction. We also characterized the phenotype regarding cell proliferation, cell migration, and cell invasion in EOC cells lines with altered expression levels of both miR-381 and its target gene, YY1. The expression levels of miR-381 were downregulated in EOC tissues and cell lines. Overexpression of miR-381 significantly inhibited EOC cell proliferation, migration, and invasion. Restoration of YY1 expression partially reversed the phenotype induced by miR-381 overexpression. Knockdown of miR-381 target gene, YY1, mimicked the phenotype induced by miR-381 overexpression. MiR-381 regulated EOC cell through miR-381/YY1/p53 and miR-381/YY1/Wnt signaling axis. We concluded that miR-381 inhibited EOC cell proliferation, migration, and invasion, at least in part, via suppressing YY1 expression.

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RANK-RANKL interactions are involved in cell adhesion-mediated drug resistance in multiple myeloma cell lines

Abstract

Interaction between multiple myeloma (MM) cells and the bone marrow microenvironment plays a critical role in MM pathogenesis and the development of drug resistance. Recently, it has been reported that MM cells express the receptor activator of nuclear factor-κB (NF-κB) (RANK). However, the role of the RANK/RANK ligand (RANKL) system in drug resistance remains unclear. In this study, we demonstrated a novel function of the RANK/RANKL system in promoting drug resistance in MM. We found that RANKL treatment induced drug resistance in RANK-expressing but not RANK-negative cell lines. RANKL stimulation of RANK-expressing cells increased multidrug resistance protein 1 (MDR1), breast cancer resistance protein (BCRP), and lung resistance protein 1 (LRP1) expression and decreased Bim expression through various signaling molecules. RNA silencing of Bim expression induced drug resistance, but the RANKL-mediated drug resistance could not be overcome through the RNA silencing of MDR1, BCRP, and LRP1 expression. These results indicate that the RANK/RANKL system induces chemoresistance through the activation of multiple signal transduction pathways and by decreasing Bim expression in RANK-positive MM cells. These findings may prove to be useful in the development of cell adhesion-mediated drug resistance inhibitors in RANK-positive MM cells.

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The lack of clinical value of peritoneal washing cytology in high risk patients undergoing risk-reducing salpingo-oophorectomy: a retrospective study and review

Abstract

Background

To assess the clinical value of peritoneal washing cytology (PWC) in women with BRCA1 or BRCA2 mutations and women from a family with hereditary breast and/or ovarian cancer (HBOC) undergoing risk-reducing salpingo-oophorectomy (RRSO) in detecting primary peritoneal cancer (PPC) or occult ovarian/fallopian tube cancer.

Methods

A retrospective study of patients with known BRCA1 or BRCA2 mutation or HBOC who underwent RRSO at the Erasmus Medical Centre, Rotterdam, The Netherlands between January 2000–2014. Patients with an elevated risk of malignancy prior to the procedure were excluded from primary analysis (elevated CA-125, an ovarian mass, abdominal pain or another gynecological malignancy). A review of the literature was conducted.

Results

Of the 471 patients who underwent RRSO, a total of 267 cytology samples were available for analysis. Four samples showed malignant cells, all four patients were diagnosed with ovarian and/or fallopian tube cancer at histologic examination. A fifth patient, of whom no cytology sample was obtained during RRSO, developed primary peritoneal cancer 80 months post RRSO.

Conclusions

This study failed to show that cytology is of value during RRSO in detecting primary peritoneal cancer, however 36 % of patients with concomitant ovarian or fallopian tube cancer had positive cytology. Therefore, the routine sampling of peritoneal washings during RRSO is not found to be useful to detect subsequent PPC.

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Twin machines validation for VMAT treatments using electronic portal-imaging device: a multicenter study

Abstract

Purpose

To verify the accuracy of volumetric arc therapy (VMAT) using the RapidArc™ device when switching patients from one single linear accelerator (linac) to a paired energy and mechanics "twin" linac without reoptimization of the original treatment plan.

Patients and Methods

Four centers using 8 linacs were involved in this study. Seventy-four patients previously treated with the 6MV photon RapidArc™ technique were selected for analysis, using 242 measurements. In each institution, all patients were planned on linac A, and their plans were verified both on linac A and on the twin linac B. Verifications were done using the amorphous silicium electronic portal imager (EPID) of the linacs and were analyzed with the EpiQa software (Epidos, Bratislavia, Slovakia). The gamma index formalism was used for validation with a double threshold of 3 % and 3 mm with a measurement resolution of 0.39 mm/pixel, and a smoothed resolution of approximately 2.5 mm.

Results

The number of points passing the gamma criteria between the measured and computed doses was 94.79 ± 2.57 % for linac A and 94.61 ± 2.46 % for linac B. Concerning the smoothed measurement analysis, 98.67 ± 1.26 % and 98.59 ± 1.20 % points passing the threshold were obtained for linacs A and B, respectively.

The difference between the 2 dose matrices acquired on the EPID was very small, with 99.92 ± 0.06 % of the points passing the criteria.

Conclusion

For linacs sharing the same mechanical and energy parameters, this study tends to indicate that patients may be safely switched from treatment with one linac to treatment with its twin linac using the same VMAT plan.

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Deciphering the anti-angiogenic effect of endostatin/cyclophosphamide to normalize tumor micrangium through notch signaling pathway in colon cancer

Abstract

Background

The invasion of colon cancer is associated with the tumor angiogenesis. Endostatin is an important anti-angiogenic agent, and the additive effect of endostatin with a chemotherapeutic agent, cyclophosphamide, on micrangium has not been established.

Methods

Male BALB/c strain nude mice were injected with human colorectal carcinoma cells (HCT-116). The mice were divided into four groups (n = 15, each group) and were treated with different concentrations of endostatin (15, 10, and 5 mg/kg/day), cyclophosphamide (20, 10, and 5 mg/kg/day), and combination of endostatin/cyclophosphamide (15 + 20, 15 + 10, and 15 + 5 mg/kg/day). The tumor inhibition rate was evaluated, followed by the quantification of messenger ribonucleic acid (mRNA) and protein expression of notch signaling components NOTCH-1, NOTCH-3, NOTCH-4, JAG-1, DLL-4, Hes-1, and Hey-1 using quantitative polymerase chain reaction (qPCR). The protein expression of NOTCH-3, JAG-1, and DLL-4 was confirmed using western blotting. Microvessel density (MVD) was evaluated to detect micrangium following the treatment.

Results

The endostatin/cyclophosphamide-treated samples exhibited an additive effect on the tumor inhibition rate and the microvessel count. NOTCH-1, NOTCH-3, NOTCH-4, JAG-1, Hes-1, and Hey-1 expression levels were highly correlated and downregulated in the treated samples, whereas DLL-4 expression was upregulated that accounted for its anti-angiogenic property.

Conclusions

The combination treatment of colon cancer with endostatin and a chemotherapeutic agent, cyclophosphamide proves to be an efficient therapeutic strategy to inhibit the rapid vasculature formation confirmed by the differential expression of notch signaling components.

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Oncology E-Learning for Undergraduate. A Prospective Randomized Controlled Trial

Abstract

The e-learning education is a promising method, but there are few prospective randomized publications in oncology. The purpose of this study was to assess the level of retention of information in oncology from undergraduate students of physiotherapy. A prospective, controlled, randomized, crossover study, 72 undergraduate students of physiotherapy, from the second to fourth years, were randomized to perform a course of physiotherapy in oncology (PHO) using traditional classroom or e-learning. Students were offered the same content of the subject. The teacher in the traditional classroom model and the e-learning students used the Articulate® software. The course tackled the main issues related to PHO, and it was divided into six modules, 18 lessons, evaluated by 126 questions. A diagnosis evaluation was performed previous to the course and after every module. The sample consisted of 67 students, allocated in groups A (n = 35) and B (n = 32), and the distribution was homogeneous between the groups. Evaluating the correct answers, we observed a limited score in the pre-test (average grade 44.6 %), which has significant (p < 0.001) improvement in post-test evaluation (average grade 73.9 %). The correct pre-test (p = 0.556) and post-test (p = 0.729) evaluation and the retention of information (p = 0.408) were not different between the two groups. The course in PHO allowed significant acquisition of knowledge to undergraduate students, but the level of information retention was statistically similar between the traditional classroom form and the e-learning, a fact that encourages the use of e-learning in oncology.

Clinical Trial Registration number

REBECU1111-1142-1963

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Urtica dioica modulates hippocampal insulin signaling and recognition memory deficit in streptozotocin induced diabetic mice

Abstract

Diabetes mellitus has been associated with functional abnormalities in the hippocampus and performance of cognitive function. Urtica dioica (UD) has been used in the treatment of diabetes. In our previous report we observed that UD extract attenuate diabetes mediated associative and spatial memory dysfunction. The present study aimed to evaluate the effect of UD extract on mouse model of diabetes-induced recognition memory deficit and explore the possible mechanism behind it. Streptozotocin (STZ) (50 mg/kg, i.p. consecutively for 5 days) was used to induce diabetes followed by UD extract (50 mg/kg, oral) or rosiglitazone (ROSI) (5 mg/kg, oral) administration for 8 weeks. STZ induced diabetic mice showed significant decrease in hippocampal insulin signaling and translocation of glucose transporter type 4 (GLUT4) to neuronal membrane resulting in cognitive dysfunction and hypolocomotion. UD treatment effectively improved hippocampal insulin signaling, glucose tolerance and recognition memory performance in diabetic mice, which was comparable to ROSI. Further, diabetes mediated oxidative stress and inflammation was reversed by chronic UD or ROSI administration. UD leaves extract acts via insulin signaling pathway and might prove to be effective for the diabetes mediated central nervous system complications.

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Mediastinal Germ Cell Tumors in Pediatric Patients: A Report From the Italian Association of Pediatric Hematology and Oncology

Background

Primary mediastinal germ cell tumors (GCTs) are rare in children and still represent a challenge for both adult and pediatric oncologists because of their worse outcome compared to their gonadal counterpart.

Procedure

Prospectively collected data concerning patients enrolled in the Italian Association of Pediatric Haematology and Oncology study on malignant GCTs (AIEOP TCGM 2004) protocol for the treatment of GCTs were analyzed. Patients with malignant mediastinal primary GCTs were included in this study. Data regarding patients with newly diagnosed mediastinal teratoma were also collected.

Results

From 2005 to 2013, 20 children diagnosed with mediastinal GCTs were registered in AIEOP TCGM 2004 protocol. With a median follow-up of 89 months (range 35–123), the overall survival (OS) and event free survival (EFS) rates were 100% for teratoma and 90% for malignant GCTs.

Conclusions

We confirm the favorable outcome of children affected by mediastinal teratoma and malignant GCTs. For malignant tumors, further studies on the clinical characteristics and genetic signatures on tumor samples might be necessary to better understand differences observed in high-risk patients and to assist the development of more effective treatment for this subgroup.

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Comment on: The UK Experience of a Treatment Strategy for Pediatric Metastatic Medulloblastoma Comprising Intensive Induction Chemotherapy, Hyperfractionated Accelerated Radiotherapy, and Response Directed High-Dose Myeloablative Chemotherapy or Maintenance Chemotherapy (Milan Strategy)

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