HPV-Induced Tumors Controlled by CD8+ Cells and MDSC Depletion

Active anticancer immunotherapeutic approaches have been shown to induce cellular or humoral immune responses in patients, but, thus far, the observed outcomes did not ensure their recommendation for clinical use. The induction of tumor-specific CD8⁺ T cells, although required for the clearance of most solid tumors, was shown to be insufficient for the development of a successful immunotherapeutic approach. The suppressive immune environment triggered by tumors, including the expansion of myeloid-derived suppressor cells (MDSC), is detrimental to the development of antitumor immune responses and precludes the generation of more promising clinical outcomes. In this work, we characterized the CD8⁺ T-cell population specifically involved in the control of tumor growth and the role of MDSCs after administration of an antitumor therapeutic DNA vaccine targeting human papillomavirus type 16 (HPV-16)-associated tumors. Activation of cytotoxic high-avidity CD8⁺ T cells with an effector memory phenotype was found in mice grafted with tumor cells expressing the HPV-16 oncoproteins. In addition, MDSC antibody depletion further enhanced the immunotherapeutic effects of the vaccine, resulting in the complete eradication of tumor cells. Collectively, the current results indicate that the simultaneous control of MDSCs and activation of high-avidity tumor-specific effector memory CD8⁺ T cells are key features for tumor protection by immunotherapeutic approaches and deserve further testing under clinical conditions. Mol Cancer Ther; 15(8); 1920–30. ©2016 AACR.

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Selected Articles from This Issue

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ATM Mutations in Cancer

Activation of checkpoint arrest and homologous DNA repair are necessary for maintenance of genomic integrity during DNA replication. Germ-line mutations of the ataxia telangiectasia mutated (ATM) gene result in the well-characterized ataxia telangiectasia syndrome, which manifests with an increased cancer predisposition, including a 20% to 30% lifetime risk of lymphoid, gastric, breast, central nervous system, skin, and other cancers. Somatic ATM mutations or deletions are commonly found in lymphoid malignancies, as well as a variety of solid tumors. Such mutations may result in chemotherapy resistance and adverse prognosis, but may also be exploited by existing or emerging targeted therapies that produce synthetic lethal states. Mol Cancer Ther; 15(8); 1781–91. ©2016 AACR.

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AKT3 and Breast Tumor Resistance

Acquired resistance to molecular targeted therapy represents a major challenge for the effective treatment of cancer. Hyperactivation of the PI3K/AKT pathway is frequently observed in virtually all human malignancies, and numerous PI3K and AKT inhibitors are currently under clinical evaluation. However, mechanisms of acquired resistance to AKT inhibitors have yet to be described. Here, we use a breast cancer preclinical model to identify resistance mechanisms to a small molecule allosteric AKT inhibitor, MK2206. Using a step-wise and chronic high-dose exposure, breast cancer cell lines harboring oncogenic PI3K resistant to MK2206 were established. Using this model, we reveal that AKT3 expression is markedly upregulated in AKT inhibitor–resistant cells. Induction of AKT3 is regulated epigenetically by the bromodomain and extra terminal domain proteins. Importantly, knockdown of AKT3, but not AKT1 or AKT2, in resistant cells restores sensitivity to MK2206. AKT inhibitor–resistant cells also display an epithelial to mesenchymal transition phenotype as assessed by alterations in the levels of E-Cadherin, N-Cadherin, and vimentin, as well as enhanced invasiveness of tumor spheroids. Notably, the invasive morphology of resistant spheroids is diminished upon AKT3 depletion. We also show that resistance to MK2206 is reversible because upon drug removal resistant cells regain sensitivity to AKT inhibition, accompanied by reexpression of epithelial markers and reduction of AKT3 expression, implying that epigenetic reprogramming contributes to acquisition of resistance. These findings provide a rationale for developing therapeutics targeting AKT3 to circumvent acquired resistance in breast cancer. Mol Cancer Ther; 15(8); 1964–74. ©2016 AACR.

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MYC and Pancreatic Cancer

Current data suggest that MYC is an important signaling hub and driver in pancreatic ductal adenocarcinoma (PDAC), a tumor entity with a strikingly poor prognosis. No targeted therapies with a meaningful clinical impact were successfully developed against PDAC so far. This points to the need to establish novel concepts targeting the relevant drivers of PDAC, like KRAS or MYC. Here, we discuss recent developments of direct or indirect MYC inhibitors and their potential mode of action in PDAC. Mol Cancer Ther; 15(8); 1792–8. ©2016 AACR.

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SYD985 in Uterine Serous Carcinoma with HER2/Neu Expression

Uterine serous carcinoma (USC) is an aggressive form of endometrial cancer. Up to 35% of USC may overexpress the HER2/neu oncogene at strong (i.e., 3+) levels by IHC while an additional 40% to 50% express HER2/neu at moderate (2+) or low (1+) levels. We investigated the efficacy of SYD985, (Synthon Biopharmaceuticals), a novel HER2-targeting antibody–drug conjugate (ADC) composed of the mAb trastuzumab linked to a highly potent DNA-alkylating agent (i.e., duocarmycin) in USC. We also compared the antitumor activity of SYD985 in head-to-head experiments to trastuzumab emtansine (T-DM1), a FDA-approved ADC, against multiple primary USC cell lines expressing different levels of HER2/neu in in vitro and in vivo experiments. Using antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability, and bystander killing assays as well as propidium iodide–based flow cytometry assays and multiple in vivo USC mouse xenograft models, we demonstrate for the first time that SYD985 is a novel ADC with activity against USC with strong (3+) as well as low to moderate (i.e., 1+/2+) HER2/neu expression. SYD985 is 10- to 70-fold more potent than T-DM1 in comparative experiments and, unlike T-DM1, it is active against USC demonstrating moderate/low or heterogeneous HER2/neu expression. Clinical studies with SYD985 in patients harboring chemotherapy-resistant USC with low, moderate, and high HER2 expression are warranted. Mol Cancer Ther; 15(8); 1900–9. ©2016 AACR.

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Radiosensitization of Medulloblastoma by Inhibition of MRK

Medulloblastoma is a cerebellar tumor and the most common pediatric brain malignancy. Radiotherapy is part of the standard care for this tumor, but its effectiveness is accompanied by significant neurocognitive sequelae due to the deleterious effects of radiation on the developing brain. We have previously shown that the protein kinase MRK/ZAK protects tumor cells from radiation-induced cell death by regulating cell-cycle arrest after ionizing radiation. Here, we show that siRNA-mediated MRK depletion sensitizes medulloblastoma primary cells to radiation. We have, therefore, designed and tested a specific small molecule inhibitor of MRK, M443, which binds to MRK in an irreversible fashion and inhibits its activity. We found that M443 strongly radiosensitizes UW228 medulloblastoma cells as well as UI226 patient–derived primary cells, whereas it does not affect the response to radiation of normal brain cells. M443 also inhibits radiation-induced activation of both p38 and Chk2, two proteins that act downstream of MRK and are involved in DNA damage–induced cell-cycle arrest. Importantly, in an animal model of medulloblastoma that employs orthotopic implantation of primary patient–derived UI226 cells in nude mice, M443 in combination with radiation achieved a synergistic increase in survival. We hypothesize that combining radiotherapy with M443 will allow us to lower the radiation dose while maintaining therapeutic efficacy, thereby minimizing radiation-induced side effects. Mol Cancer Ther; 15(8); 1799–808. ©2016 AACR.

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AR in CD4+ T Cells Conducted Bladder Cancer Tumor Microenvironment

The tumor microenvironment impacts tumor progression and individual cells, including CD4⁺ T cells, which have been detected in bladder cancer tissues. The detailed mechanism of how these T cells were recruited to the bladder cancer tumor and their impact on bladder cancer progression, however, remains unclear. Using a human clinical bladder cancer sample survey and in vitro coculture system, we found that bladder cancer has a greater capacity to recruit T cells than surrounding normal bladder tissues. The consequences of higher levels of recruited T cells in bladder cancer included increased bladder cancer metastasis. Mechanism dissection revealed that infiltrating T cells might function through secreting the cytokine IL1, which increases the recruitment of T cells to bladder cancer and enhances the bladder cancer androgen receptor (AR) signaling that results in increased bladder cancer cell invasion via upregulation of hypoxia-inducible factor-1α (HIF1α)/VEGFa expression. Interruption of the IL1->AR->HIF1α->VEGFa signals with inhibitors of HIF1α or VEGFa partially reversed the enhanced bladder cancer cell invasion. Finally, in vivo mouse models of xenografted bladder cancer T24 cells with CD4⁺ T cells confirmed in vitro coculture studies and concluded that infiltrating CD4⁺ T cells can promote bladder cancer metastasis via modulation of the IL1->AR->HIF1α->VEGFa signaling. Future clinical trials using small molecules to target this newly identified signaling pathway may facilitate the development of new therapeutic approaches to better suppress bladder cancer metastasis. Mol Cancer Ther; 15(8); 1943–51. ©2016 AACR.

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MLN8237 plus Eribulin Eradicates Metastases via Autophagy

Recent findings suggest that the inhibition of Aurora A (AURKA) kinase may offer a novel treatment strategy against metastatic cancers. In the current study, we determined the effects of AURKA inhibition by the small molecule inhibitor MLN8237 both as a monotherapy and in combination with the microtubule-targeting drug eribulin on different stages of metastasis in triple-negative breast cancer (TNBC) and defined the potential mechanism of its action. MLN8237 as a single agent and in combination with eribulin affected multiple steps in the metastatic process, including migration, attachment, and proliferation in distant organs, resulting in suppression of metastatic colonization and recurrence of cancer. Eribulin application induces accumulation of active AURKA in TNBC cells, providing foundation for the combination therapy. Mechanistically, AURKA inhibition induces cytotoxic autophagy via activation of the LC3B/p62 axis and inhibition of pAKT, leading to eradication of metastases, but has no effect on growth of mammary tumor. Combination of MLN8237 with eribulin leads to a synergistic increase in apoptosis in mammary tumors, as well as cytotoxic autophagy in metastases. These preclinical data provide a new understanding of the mechanisms by which MLN8237 mediates its antimetastatic effects and advocates for its combination with eribulin in future clinical trials for metastatic breast cancer and early-stage solid tumors. Mol Cancer Ther; 15(8); 1809–22. ©2016 AACR.

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Afatinib for ESCC or HNSCC

The prognosis for patients with advanced esophageal or head-and-neck squamous cell carcinoma (ESCC or HNSCC) remains poor, and the identification of additional oncogenes and their inhibitors is needed. In this study, we evaluated the sensitivities of several ESCC and HNSCC cell lines to HER inhibitors (cetuximab, erlotinib, and afatinib) in vitro and found two cell lines that were hypersensitive to afatinib. Sequence analyses for the afatinib-targeted HER family genes in the two cell lines revealed that one cell line had a previously reported activating EGFR L861Q mutation, whereas the other had an HER4 G1109C mutation of unknown function. No amplification of HER family genes was found in either of the two cell lines. The phosphorylation level of HER4 was elevated in the HER4 G1109C mutation-overexpressed HEK293 cell line, and the mutation had a transforming potential and exhibited tumorigenicity in an NIH3T3 cell line, indicating that this HER4 mutation was an activating oncogenic mutation. Afatinib dramatically reduced the phosphorylation level of EGFR or HER4 and induced apoptosis in the two cell lines. In vivo, tumor growth was also dramatically decreased by afatinib. In a database, the frequencies of HER family gene mutations in ESCC or HNSCC ranged from 0% to 5%. In particular, HER4 mutations have been found relatively frequently in HNSCC. Considering the addiction of cancer cells to activating oncogenic EGFR or HER4 mutations for proliferation, HNSCC or ESCC with such oncogenic mutations might be suitable for targeted therapy with afatinib. Mol Cancer Ther; 15(8); 1988–97. ©2016 AACR.

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BET Inhibitors for Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is an incurable disease with poor prognosis. At this moment, therapeutic options are limited to chemotherapy, and no targeted agent has reached the clinical setting. Bromodomain and extraterminal (BET) inhibitors are a new family of compounds that inhibit bromodomain-containing proteins affecting the expression of transcription factors, therefore modifying the expression of relevant oncogenic genes. In the present article, by using an in silico approach, we have identified the expression of upregulated transcription factors in TNBC compared with normal breast. Treatment with JQ1, a well-characterized BET inhibitor, modified some transcription factors, including DEP domain containing 1 (DEPDC), Forkhead box M1 (FOXM1), and Lim domain only 4 (LM04). In cell line models, administration of JQ1 or OTX015, another BET inhibitor, produced a significant antiproliferative effect and synergized with chemotherapies. Biochemical evaluation demonstrated an arrest at G₁ as the main mechanism of action with a clear increase of p27. Addition of these compounds to chemotherapy induced apoptosis compared to each agent given alone. Evaluation of JQ1 in xenografted tumors in nude mice showed a profound antitumoral effect with a reduction of DEPDC, FOXM1, and LM04, in addition to an increase of p27. Globally, our data demonstrate the antitumor effect of this new family of compounds in TNBC, paving the way for its future clinical development. Mol Cancer Ther; 15(8); 1823–33. ©2016 AACR.

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A New Anti-CXCR4 Antibody

The type IV C-X-C-motif chemokine receptor (CXCR4) is expressed in a large variety of human cancers, including hematologic malignancies, and this receptor and its ligand, stromal cell–derived factor-1 (SDF-1), play a crucial role in cancer progression. We generated a humanized immunoglobulin G1 mAb, hz515H7, which binds human CXCR4, efficiently competes for SDF-1 binding, and induces a conformational change in CXCR4 homodimers. Furthermore, it inhibits both CXCR4 receptor–mediated G-protein activation and β-arrestin-2 recruitment following CXCR4 activation. The binding of the hz515H7 antibody to CXCR4 inhibits the SDF-1–induced signaling pathway, resulting in reduced phosphorylation of downstream effectors, such as Akt, Erk1/2, p38, and GSK3β. Hz515H7 also strongly inhibits cell migration and proliferation and, while preserving normal blood cells, induces both antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against neoplastic cells. In mouse xenograft models, hz515H7 displays antitumor activities with multiple hematologic tumor cell lines, with its Fc-mediated effector functions proving essential in this context. Furthermore, hz515H7 binds to primary tumor cells from acute myeloid leukemia and multiple myeloma patients. Collectively, our results demonstrate two major mechanisms of action, making hz515H7 unique in this regard. Its potential as a best-in-class molecule is currently under investigation in a phase I clinical trial. Mol Cancer Ther; 15(8); 1890–9. ©2016 AACR.

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Targeted PDT Treatment of Prostate Cancer

Prostatectomy has been the mainstay treatment for men with localized prostate cancer. Surgery, however, often can result in major side effects, which are caused from damage and removal of nerves and muscles surrounding the prostate. A technology that can help surgeons more precisely identify and remove prostate cancer resulting in a more complete prostatectomy is needed. Prostate-specific membrane antigen (PSMA), a type II membrane antigen highly expressed in prostate cancer, has been an attractive target for imaging and therapy. The objective of this study is to develop low molecular weight PSMA-targeted photodynamic therapy (PDT) agents, which would provide image guidance for prostate tumor resection and allow for subsequent PDT to eliminate unresectable or remaining cancer cells. On the basis of our highly negatively charged, urea-based PSMA ligand PSMA-1, we synthesized two PSMA-targeting PDT conjugates named PSMA-1-Pc413 and PSMA-1-IR700. In in vitro cellular uptake experiments and in vivo animal imaging experiments, the two conjugates demonstrated selective and specific uptake in PSMA-positive PC3pip cells/tumors, but not in PSMA-negative PC3flu cells/tumors. Further in vivo photodynamic treatment proved that the two PSMA-1–PDT conjugates can effectively inhibit PC3pip tumor progression. The two PSMA-1–PDT conjugates reported here may have the potential to aid in the detection and resection of prostate cancers. It may also allow for the identification of unresectable cancer tissue and PDT ablation of such tissue after surgical resection with potentially less damage to surrounding tissues. Mol Cancer Ther; 15(8); 1834–44. ©2016 AACR.

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Overcoming SN-38-ADC Drug Resistance

Sacituzumab govitecan (IMMU-132), an SN-38–conjugated antibody–drug conjugate, is showing promising therapeutic results in a phase I/II trial of patients with advanced Trop-2–expressing, metastatic, solid cancers. As members of the ATP-binding cassette (ABC) transporters confer chemotherapy resistance by active drug efflux, which is a frequent cause of treatment failure, we explored the use of known inhibitors of ABC transporters for improving the therapeutic efficacy of IMMU-132 by overcoming SN-38 resistance. Two human tumor cell lines made resistant to SN-38, MDA-MB-231-S120 (human breast cancer) and NCI-N87-S120 (human gastric cancer), were established by continuous exposure of the parental cells to stepwise increased concentrations of SN-38 and analyzed by flow cytometry for functional activities of ABCG2 and ABCB1, immunoblotting and qRT-PCR for the expression of ABCG2 at both protein and mRNA levels, and MTS assays for the potency of SN-38 alone or in combination with a modulator of ABC transporters. MDA-MB-231-S120 and NCI-N87-S120 displayed reduced sensitivity to SN-38 in vitro, with IC₅₀ values approximately 50-fold higher than parental MDA-MB-231 and NCI-N87 cells. The increase in drug resistance of both S120 cell populations is associated with the expression of functional ABCG2, but not ABCB1. Importantly, treatment of both S120 sublines with known ABCG2 inhibitors (fumitremorgin C, Ko143, and YHO-13351) restored toxicity of SN-38, and the combination of YHO-13351 with IMMU-132 increased the median survival of mice bearing NCI-N87-S120 xenografts. These results provide a rationale for combination therapy of IMMU-132 and inhibitors of ABC transporters, such as YHO-13351. Mol Cancer Ther; 15(8); 1910–9. ©2016 AACR.

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Reversal of MDR by Osimertinib

The overexpression of ATP-binding cassette (ABC) transporters has been proved to be a major trigger for multidrug resistance (MDR) in certain types of cancer. In our study, we investigated whether osimertinib (AZD9291), a third-generation irreversible tyrosine kinase inhibitor of both activating EGFR mutations and resistance-associated T790M point mutation, could reverse MDR induced by ABCB1 and ABCG2 in vitro, in vivo, and ex vivo. Our results showed that osimertinib significantly increased the sensitivity of ABCB1- and ABCG2-overexpressing cells to their substrate chemotherapeutic agents in vitro and in the model of ABCB1-overexpressing KBv200 cell xenograft in nude mice. Mechanistically, osimertinib increased the intracellular accumulations of doxorubicin (DOX) and Rhodamine 123 (Rho 123) by inhibiting the efflux function of the transporters in ABCB1- or ABCG2-overexpressing cells but not in their parental sensitive cells. Furthermore, osimertinib stimulated the ATPase activity of both ABCB1 and ABCG2 and competed with the [¹²⁵I] iodoarylazidoprazosin photolabeling bound to ABCB1 or ABCG2, but did not alter the localization and expression of ABCB1 or ABCG2 in mRNA and protein levels nor the phosphorylations of EGFR, AKT, and ERK. Importantly, osimertinib also enhanced the cytotoxicity of DOX and intracellular accumulation of Rho 123 in ABCB1-overexpressing primary leukemia cells. Overall, these findings suggest osimertinib reverses ABCB1- and ABCG2-mediated MDR via inhibiting ABCB1 and ABCG2 from pumping out chemotherapeutic agents and provide possibility for cancer combinational therapy with osimertinib in the clinic. Mol Cancer Ther; 15(8); 1845–58. ©2016 AACR.

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Emodin Blocks Cancer Cell-Macrophage Interaction

Macrophage infiltration correlates with severity in many types of cancer. Tumor cells recruit macrophages and educate them to adopt an M2-like phenotype through the secretion of chemokines and growth factors, such as MCP1 and CSF1. Macrophages in turn promote tumor growth through supporting angiogenesis, suppressing antitumor immunity, modulating extracellular matrix remodeling, and promoting tumor cell migration. Thus, tumor cells and macrophages interact to create a feedforward loop supporting tumor growth and metastasis. In this study, we tested the ability of emodin, a Chinese herb–derived compound, to inhibit breast cancer growth in mice and examined the underlying mechanisms. Emodin was used to treat mice bearing EO771 or 4T1 breast tumors. It was shown that emodin attenuated tumor growth by inhibiting macrophage infiltration and M2-like polarization, accompanied by increased T-cell activation and reduced angiogenesis in tumors. The tumor inhibitory effects of emodin were lost in tumor-bearing mice with macrophage depletion. Emodin inhibited IRF4, STAT6, and C/EBPβ signaling and increased inhibitory histone H3 lysine 27 tri-methylation (H3K27m3) on the promoters of M2-related genes in tumor-associated macrophages. In addition, emodin inhibited tumor cell secretion of MCP1 and CSF1, as well as expression of surface anchoring molecule Thy-1, thus suppressing macrophage migration toward and adhesion to tumor cells. These results suggest that emodin acts on both breast cancer cells and macrophages and effectively blocks the tumor-promoting feedforward loop between the two cell types, thereby inhibiting breast cancer growth and metastasis. Mol Cancer Ther; 15(8); 1931–42. ©2016 AACR.

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Vemurafenib and PAC-1 Are Synergistic in Mutant BRAF Melanomas

The development of vemurafenib resistance limits the long-term efficacy of this drug for treatment of metastatic melanomas with the ^V600EBRAF mutation. Inhibition of downstream MAPK signaling with vemurafenib induces apoptotic cell death mediated by caspase-3, suggesting that addition of a procaspase-3 activator could enhance anticancer effects. Here, we show that the combination of PAC-1, a procaspase-activating compound, and vemurafenib is highly synergistic in enhancing caspase-3 activity and apoptotic cell death in melanoma cell lines harboring the ^V600EBRAF mutation. In vivo, the combination displays a favorable safety profile in mice and exerts significant antitumor effects. We further demonstrate that addition of PAC-1 to the clinically useful combination of vemurafenib and a MEK inhibitor, trametinib, starkly enhances the caspase-3 activity and proapoptotic effect of the combination. Moreover, addition of low concentration PAC-1 also delays the regrowth of cells following treatment with vemurafenib. Finally, PAC-1 remains potent against vemurafenib-resistant A375VR cells in cell culture and synergizes with vemurafenib to exert antitumor effects on A375VR cell growth in vivo. Collectively, our data suggest that inhibition of MAPK signaling combined with concurrent procaspase-3 activation is an effective strategy to enhance the antitumor activity of vemurafenib and mitigate the development of resistance. Mol Cancer Ther; 15(8); 1859–69. ©2016 AACR.

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The MAPK Pathway Facilitates Resistance to Dasatinib

Advanced stages of papillary and anaplastic thyroid cancer represent a highly aggressive subset, in which there are currently few effective therapies. We and others have recently demonstrated that c-SRC is a key mediator of growth, invasion, and metastasis, and therefore represents a promising therapeutic target in thyroid cancer. However, clinically, Src inhibitor efficacy has been limited, and therefore further insights are needed to define resistance mechanisms and determine rational combination therapies. We have generated four thyroid cancer cell lines with a greater than 30-fold increase in acquired resistance to the Src inhibitor dasatinib. Upon acquisition of dasatinib resistance, the two RAS-mutant cell lines acquired the c-SRC gatekeeper mutation (T341M), whereas the two BRAF-mutant cell lines did not. Accordingly, Src signaling was refractory to dasatinib treatment in the RAS-mutant dasatinib-resistant cell lines. Interestingly, activation of the MAPK pathway was increased in all four of the dasatinib-resistant cell lines, likely due to B-Raf and c-Raf dimerization. Furthermore, MAP2K1/MAP2K2 (MEK1/2) inhibition restored sensitivity in all four of the dasatinib-resistant cell lines, and overcame acquired resistance to dasatinib in the RAS-mutant Cal62 cell line, in vivo. Together, these studies demonstrate that acquisition of the c-SRC gatekeeper mutation and MAPK pathway signaling play important roles in promoting resistance to the Src inhibitor dasatinib. We further demonstrate that up-front combined inhibition with dasatinib and MEK1/2 or ERK1/2 inhibitors drives synergistic inhibition of growth and induction of apoptosis, indicating that combined inhibition may overcome mechanisms of survival in response to single-agent inhibition. Mol Cancer Ther; 15(8); 1952–63. ©2016 AACR.

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ADCs with Potent DNA Alkylating Agents

The promise of tumor-selective delivery of cytotoxic agents in the form of antibody–drug conjugates (ADC) has now been realized, evidenced by the approval of two ADCs, both of which incorporate highly cytotoxic tubulin-interacting agents, for cancer therapy. An ongoing challenge remains in identifying potent agents with alternative mechanisms of cell killing that can provide ADCs with high therapeutic indices and favorable tolerability. Here, we describe the development of a new class of potent DNA alkylating agents that meets these objectives. Through chemical design, we changed the mechanism of action of our novel DNA cross-linking agent to a monofunctional DNA alkylator. This modification, coupled with linker optimization, generated ADCs that were well tolerated in mice and demonstrated robust antitumor activity in multiple tumor models at doses 1.5% to 3.5% of maximally tolerated levels. These properties underscore the considerable potential of these purpose-created, unique DNA-interacting conjugates for broadening the clinical application of ADC technology. Mol Cancer Ther; 15(8); 1870–8. ©2016 AACR.

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Targeting ERK1 in DC Vaccines for Glioma

Glioma regression requires the recruitment of potent antitumor immune cells into the tumor microenvironment. Dendritic cells (DC) play a role in immune responses to these tumors. The fact that DC vaccines do not effectively combat high-grade gliomas, however, suggests that DCs need to be genetically modified specifically to promote their migration to tumor relevant sites. Previously, we identified extracellular signal–regulated kinase (ERK1) as a regulator of DC immunogenicity and brain autoimmunity. In the current study, we made use of modern magnetic resonance methods to study the role of ERK1 in regulating DC migration and tumor progression in a model of high-grade glioma. We found that ERK1-deficient mice are more resistant to the development of gliomas, and tumor growth in these mice is accompanied by a higher infiltration of leukocytes. ERK1-deficient DCs exhibit an increase in migration that is associated with sustained Cdc42 activation and increased expression of actin-associated cytoskeleton-organizing proteins. We also demonstrated that ERK1 deletion potentiates DC vaccination and provides a survival advantage in high-grade gliomas. Considering the therapeutic significance of these results, we propose ERK1-deleted DC vaccines as an additional means of eradicating resilient tumor cells and preventing tumor recurrence. Mol Cancer Ther; 15(8); 1975–87. ©2016 AACR.

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Clinical features and prognosis of patients with myelodysplastic syndromes who were exposed to atomic bomb radiation in Nagasaki

Summary

There is evidence that radiation exposure is a causative factor of myelodysplastic syndromes (MDS). However, little is known about whether radiation exposure is also a prognostic factor of MDS. We investigated the impact of radiation exposure on the prognosis of MDS occurred in Nagasaki atomic bomb survivors, by allowing for the International Prognostic Scoring System (IPSS) and the revised version (IPSS-R). Subjects were 140 patients with primary MDS diagnosed during 1985–2011 and evaluable for IPSS, IPSS-R and exposure-distance. Of those, 31 were exposed at < 1.5 km; 35 at 1.5–2.99 km, and 74 at ≥ 3.0 km. By the end of March 2014, 47 patients (34%) progressed to overt leukemia and 106 (75.7%) died. By comparing with patients exposed at ≥ 3.0 km, those exposed at < 1.5 km had significantly higher frequencies of abnormal chromosome (P = 0.02), intermediate / poor IPSS, and intermediate / poor / very poor IPSS-R cytogenetic category (P = 0.0001, and P < 0.0001, respectively). As with de novo MDS, multivariate Cox regression analyses revealed that cytogenetic abnormalities, IPSS karyotype, and IPSS-R cytogenetics were significantly associated with poor survival, and cumulative incidence of leukemic transformation in MDS among atomic bomb survivors, but exposure distance was not associated with any poor outcomes. These suggest that exposure to the greater dose of atomic bomb radiation is associated with developing poor cytogenetic abnormalities in MDS, which might consequently lead to transform overt leukemia among atomic bomb survivors.

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FBXW7 is involved in the acquisition of the malignant phenotype in epithelial ovarian tumors

Summary

FBXW7 is a ubiquitin ligase that mediates ubiquitylation of oncoproteins, such as c-Myc, cyclin E, Notch, and c-Jun. FBXW7 is a known tumor-suppressor gene, and mutations in FBXW7 have been reported in various human malignancies. In this study, we examined the sequences of the FBXW7 and p53 genes in 57 ovarian cancer clinical samples. Interestingly, we found no FBXW7 mutations associated with amino acid changes. We also investigated FBXW7 expression levels in 126 epithelial ovarian tumors. FBXW7 expression was negatively correlated with the malignant potential of ovarian tumors. That is to say, FBXW7 expression levels in ovarian cancer samples were significantly lower than those in borderline and benign tumors (p < 0.01). FBXW7 expression levels in serous carcinoma samples were the lowest among four major histological subtypes. In addition, p53-mutated ovarian cancer samples showed significantly lower levels of FBXW7 expression compared with p53 wild-type cancer samples (p < 0.001). DNA methylation arrays and bisulfite PCR sequencing experiments revealed that 5′-upstream regions of FBXW7 gene in p53-mutated samples were significantly higher methylated compared with those in p53 wild-type samples (p < 0.01). This data indicates that p53 mutations might suppress FBXW7 expression through DNA hypermethylation of FBXW7 5′-upstream regions. Thus, FBXW7 expression was downregulated in ovarian cancers, and was associated with p53 mutations and the DNA methylation status of the 5′-upstream regions of FBXW7.

This article is protected by copyright. All rights reserved.

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Prevalence and profile of cognitive impairment in adult glioma: a sensitivity analysis

Abstract

Cognitive impairment has been reported in 27–83 % of adults with World Health Organization (WHO) grade I–III glioma. However, the few studies in this field used different methods for cognitive assessment. The objective of the present study was to establish the prevalence of cognitive impairment in patients with WHO grade I–III primary brain tumors and determine the effect sizes of a comprehensive battery of tests. This study used a comprehensive neuropsychological battery to examine 27 patients. To control for false positives, prevalence was estimated from the overall neuropsychological score. Size effects were determined using Cohen's d. Cognitive impairment was observed in 51.9 % (95 % CI 33−70.7 %) of the patients; the impairment affected action speed (38.5 %), cognitive (33 %) and behavioral (21.7 %) executive functions, oral expression (29.6 %), episodic memory (29.6 %) and visuoconstructive abilities (19.2 %). The largest effect sizes (d ≥ 1.645) were observed for the Digit Symbol Substitution test, global hypoactivity, free recall, Stroop time, the Boston Naming test (BNT), the Trail Making test B (TMTB), verbal fluency and the Rey–Osterrieth Complex Figure Test. Four of these scores (global hypoactivity, the Digit Symbol Substitution test, the TMTB perseveration, and the BNT) were combined to make a shortened battery (AUC 0.872; 95 % CI 0.795–0.949). The overall neuropsychological score was the sole factor associated with the functional outcome. Our results suggest that about half of survivors with a grade I–III primary brain tumor suffer from cognitive impairment. Tests with a large effect size should be included in future large-scale studies.

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BRM Polymorphisms, Pancreatic Cancer Risk and Survival

Abstract

Variant alleles of two promoter polymorphisms in the BRM gene (BRM-741, BRM-1321), create MEF2D transcription binding sites that lead to epigenetic silencing of BRM, the key catalytic component of the SWI/SNF chromatin remodeling complex. BRM suppression can be reversed pharmacologically¹. Our group and others have reported associations with lung, head and neck, hepatocellular cancer risk^1-3, and with lung and esophageal cancer prognosis (ASCO 2013; abstract 11057 & 4077). Herein, we assessed risk and survival associations with pancreatic cancer. A provincial population-based case-control study was conducted with 623 histologically-confirmed pancreatic adenocarcinoma cases and 1192 age/gender distribution-matched controls⁴. Survival of cases was obtained through the Ontario Cancer Registry. Logistic and Cox proportional hazard regression models were fitted, adjusting for relevant covariates. Median age was 65 y; 52% were male; Stage I (8%), II (55%), III (14%), IV (23%); 53% after curative resection, 79% after chemotherapy; and 83% had died. In the risk analysis, adjusted odds ratios (aOR) were 1.01 (95%CI:0.1-2.0) and 0.96 (95%CI:0.7-1.3) for the homozygotes of BRM-741 and BRM-1321, respectively; aOR of double-homozygotes was 1.11 (95%CI:0.80-1.53), compared to the double-wildtype. For the survival analysis, adjusted hazard ratios (aHR) were 2.19 (95%CI: 1.9-2.5) for BRM-741 and 1.94 (95%CI: 1.7-2.2) for BRM-1321, per unit increase in variant alleles. Compared with the double-wildtype, aHR for carrying no, one, and two double-homozygotes were 2.14 (95%CI:1.6-2.8), 4.17 (95%CI:3.0-5.7), 8.03 (95%CI: 5.7-11.4), respectively. In conclusion, two functional promoter BRM polymorphisms were not associated with pancreatic adenocarcinoma risk, but are strongly associated with survival. This article is protected by copyright. All rights reserved.

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Worse quality of life in young and recently-diagnosed breast cancer survivors compared to female survivors of other cancers: A cross-sectional study

ABSTRACT

Literature focusing on health-related quality of life (HRQoL) by cancer site among women only is scarce. This study examines HRQoL of breast cancer (BC) survivors compared with female survivors of other cancers, and to understand which subgroups of BC survivors were particularly at risk of reduced HRQoL. We placed emphasis on young (<50 years) and recently diagnosed (≤5 years) survivors, where the deficits in HRQoL were most pronounced.The cross-sectional study consisted of 2,224 BC survivors, 8,504 non-cancer controls and 2,205 other cancer survivors in the Karma study. We examined HRQoL differences using linear regression analyses in the whole cohort and in a subset of young and recently diagnosed BC survivors (n=242) and female survivors of other cancers (n=140) with comparable ages at diagnosis (43.6 vs 43.6, p=0.917) and time since diagnosis (2.3 vs 2.8 years, p<0.001). HRQoL was assessed using the EORTC QLQ-C30 questionnaire. While only cognitive functioning was significantly compromised in BC survivors compared to survivors of other cancers when women of all ages were included, young BC survivors reported significantly lower HRQoL on multiple functional scales (global quality of life, emotional, role, social, and cognitive functioning) and experienced more fatigue and insomnia. BC survivors with any prior medical history of mental disorders reported poorer HRQoL than those without such a history. We also observed a close-knit relationship between tumor and treatment characteristics. BC survivors perform poorly in HRQoL in comparison to female survivors of other cancers. Our results emphasize the importance of age- and gender-appropriate comparison groups. This article is protected by copyright. All rights reserved.

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LAT1 is a Putative Therapeutic Target in Endometrioid Endometrial Carcinoma

ABSTRACT

L-type amino acid transporters (LAT1-4) are expressed in various cancer types and are involved in the uptake of essential amino acids such as leucine. Here we investigated the expression of LAT1-4 in endometrial adenocarcinoma and evaluated the contribution of LATs to endometrial cancer cell growth. Analysis of human gene expression data showed that all four LAT family members are expressed in endometrial adenocarcinomas. LAT1 was the most highly expressed, and showed a significant increase in both serous and endometrioid subtypes compared to normal endometrium. Endometrioid patients with the highest LAT1 levels exhibited the lowest disease-free survival. The pan-LAT inhibitor BCH led to a significant decrease in cell growth and spheroid area in four endometrial cancer cell lines tested in vitro. Knockdown of LAT1 by shRNA inhibited cell growth in HEC1A and Ishikawa cells, as well as inhibiting spheroid area in HEC1A cells. These data show that LAT1 plays an important role in regulating the uptake of essential amino acids such as leucine into endometrial cancer cells. Increased ability of BCH compared to LAT1 shRNA at inhibiting Ishikawa spheroid area suggests that other LAT family members may also contribute to cell growth. LAT1 inhibition may offer an effective therapeutic strategy in endometrial cancer patients whose tumours exhibit high LAT1 expression. This article is protected by copyright. All rights reserved.

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Prevalence and profile of cognitive impairment in adult glioma: a sensitivity analysis

Abstract

Cognitive impairment has been reported in 27–83 % of adults with World Health Organization (WHO) grade I–III glioma. However, the few studies in this field used different methods for cognitive assessment. The objective of the present study was to establish the prevalence of cognitive impairment in patients with WHO grade I–III primary brain tumors and determine the effect sizes of a comprehensive battery of tests. This study used a comprehensive neuropsychological battery to examine 27 patients. To control for false positives, prevalence was estimated from the overall neuropsychological score. Size effects were determined using Cohen's d. Cognitive impairment was observed in 51.9 % (95 % CI 33−70.7 %) of the patients; the impairment affected action speed (38.5 %), cognitive (33 %) and behavioral (21.7 %) executive functions, oral expression (29.6 %), episodic memory (29.6 %) and visuoconstructive abilities (19.2 %). The largest effect sizes (d ≥ 1.645) were observed for the Digit Symbol Substitution test, global hypoactivity, free recall, Stroop time, the Boston Naming test (BNT), the Trail Making test B (TMTB), verbal fluency and the Rey–Osterrieth Complex Figure Test. Four of these scores (global hypoactivity, the Digit Symbol Substitution test, the TMTB perseveration, and the BNT) were combined to make a shortened battery (AUC 0.872; 95 % CI 0.795–0.949). The overall neuropsychological score was the sole factor associated with the functional outcome. Our results suggest that about half of survivors with a grade I–III primary brain tumor suffer from cognitive impairment. Tests with a large effect size should be included in future large-scale studies.

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Long-Term Results on the Efficacy of Argon Plasma Coagulation for Patients with Chronic Radiation Proctitis after Conventionally Fractionated, Dose-Escalated Radiotherapy for Prostate Cancer

Publication date: Available online 1 August 2016
Source:Practical Radiation Oncology
Author(s): Joseph Weiner, David Schwartz, Manuel Martinez, Joseph Safdieh, Ayse Aytaman, David Schreiber
PurposeTo assess the efficacy and outcomes of argon plasma coagulation in the management of chronic radiation proctitis after conventionally fractionated, dose-escalated radiation therapy (≥7560cGy).Methods and Materials.We retrospectively reviewed the charts on all patients treated with external beam radiation therapy (minimum dose 7560cGy) for histologically confirmed prostate cancer at our institution from 2003 to 2011. Five hundred patients met these criteria and of these 35 patients (7.0%) developed radiation proctitis necessitating intervention with APC. Indications for APC treatment were either the need for blood transfusions due to proctitis-related anemia or refractory bleeding despite medical management.ResultsThe median follow up from the completion of radiation treatment was 78months (range 19–129) and the median follow up from the most recent APC treatment was 56months (range 3–112). Fifteen men (42.9%) needed blood transfusions due to proctitis related anemia. For 19 patients (54.3%), bleeding was controlled after one or two treatments. Eventual bleeding control was obtained in 30 patients (85.7%). The median number of sessions per patient was 2 (range 1–13). Post-APC ulceration was noted in 8 cases (22.9%). Two patients (5.7%) developed colovesicular fistulas, with one patient dying from this complication. Short interval between treatments (≤35days) was associated with an increased risk of ulcer or fistula formation.ConclusionsAPC is an effective treatment for patients with medically refractive radiation proctitis after dose-escalated radiotherapy, frequently controlling bleeding after only one or two sessions. However, rectal ulceration is a common complication, along with a small risk of life-threatening toxicity.



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Online Patient Information from Radiation Oncology Departments is too Complex for the General Population

Publication date: Available online 1 August 2016
Source:Practical Radiation Oncology
Author(s): Stephen A. Rosenberg, David M. Francis, Craig R. Hullet, Zachary S. Morris, Jeffrey V. Brower, Bethany M. Anderson, Kristin A. Bradley, Michael Bassetti, Randall J. Kimple
PurposeNearly two-thirds of cancer patients seek information about their diagnosis online. We assessed the readability of online patient education materials found on academic radiation oncology department websites to determine whether they adhered to guidelines suggesting that information be presented at a 6th grade reading level.Materials/Methods.The Association of American Medical Colleges (AAMC) website was utilized to identify all academic radiation oncology departments in the United States. One-third of these department websites were selected for analysis using a random number generator. Both general information on radiation therapy and specific information regarding various radiation modalities were collected. To test the hypothesis that the readability of these online educational materials was written at the recommended grade level, a panel of ten common readability tests was employed. A composite grade level of readability was constructed using the eight readability measures that provide a single grade level output.ResultsA mean of 5605 words (range 2058–12,837) from thirty department websites was collected. Using the composite grade level score, the overall mean readability level was determined to be 13.36 (12.83–13.89), corresponding to a collegiate reading level. This was significantly higher than the target 6th grade reading level (middle school, t (29)=27.41, p<0.001).ConclusionsOnline patient educational materials from academic radiation oncology websites are significantly more complex than recommended by the NIH and the Department of Health and Human Services. To improve patients' comprehension of radiotherapy and its role in their treatment our analysis suggests that the language used in online patient information should be simplified to communicate the information at a more appropriate level.



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The calpain inhibitor calpeptin suppresses pancreatic cancer by disrupting cancer-stromal interactions in a mouse xenograft model

Abstract

Desmoplasia contributes to the aggressive behavior of pancreatic cancer. However, recent clinical trials testing several anti-fibrotic agents on pancreatic cancer have not shown clear efficacy. Therefore, further investigation of desmoplasia-targeting anti-fibrotic agents by another mechanism is needed. Calpeptin, an inhibitor of calpains, suppressed fibroblast function and inhibited fibrosis. In this study, we investigated the anticancer effects of calpeptin on pancreatic cancer. We investigated whether calpeptin inhibited tumor progression using a mouse xenograft model. We performed quantitative RT-PCR to evaluate the expression of calpain-1 and calpain-2 mRNA in pancreatic cancer cells (PCC) and pancreatic stellate cells (PSC). We also performed functional assays, including proliferation, migration, and invasion, to evaluate the inhibitory effects of calpeptin on PCCs and PSCs. Quantitative RT-PCR demonstrated that PCCs and PSCs expressed calpain-2 mRNA. Calpeptin reduced tumor volume (P = 0.0473) and tumor weight (P = 0.0471) and inhibited the tumor desmoplastic reaction (P < 0.001) in xenograft tumors in nude mice. Calpeptin also inhibited the biologic functions of PCCs and PSCs including proliferation (P = 0.017), migration (P = 0.027), and invasion (P = 0.035) in vitro. Furthermore, calpeptin reduced the migration of PCCs and PSCs by disrupting the cancer-stromal interaction (P = 0.0002). Our findings indicate that calpeptin is a promising antitumor agent for pancreatic cancer, due to not only its suppressive effect on PCCs and PSC but also its disruption of the cancer-stromal interaction.

This article is protected by copyright. All rights reserved.

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Accelerating target discovery using pre-competitive open science— patients need faster innovation more than anyone else

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Cancers, Vol. 8, Pages 74: The Role of the C-Clamp in Wnt-Related Colorectal Cancers

T-cell Factor/Lymphoid Enhancer Factor (TCF/LEF) transcription factors are major regulators of Wnt targets, and the products of the TCF7 and TCF7L2 genes have both been implicated in the progression of colorectal cancer in animal models and humans. TCFs recognize specific DNA sequences through their high mobility group (HMG) domains, but invertebrate TCFs and some isoforms of vertebrate TCF7 and TCF7L2 contain a second DNA binding domain known as the C-clamp. This review will cover the basic properties of C-clamps and their importance in Wnt signaling, using data from Drosophila, C. elegans, and mammalian cell culture. The connection between C-clamp containing TCFs and colorectal cancer will also be discussed.

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Cancer risk in siblings of children with congenital malformations

Publication date: October 2016
Source:Cancer Epidemiology, Volume 44
Author(s): Yuelian Sun, Chun Sen Wu, Onyebuchi A. Arah, Jørn Olsen
PurposeCancer and birth defects cluster in families more often than expected by chance, but the reasons are neither well known nor well studied.MethodsFrom singletons born alive in Denmark between 1 January 1977 and 31 December 2007, we identified children who had no congenital malformations but had a full or half sibling with a congenital malformation (CM) diagnosed in the first year of life; this constituted the exposed group, while children whose siblings had no such condition constituted a reference group. We estimated cancer risks for children who had a full sibling or a half sibling with a CM using a Cox proportional hazards regression model. To control for confounding related to change of family structure, we estimated cancer risks for children from core families and children from broken families separately. Children were followed from birth up to 30 years of age (median follow-up 13.6 years). We obtained information on CMs and cancer from the Danish National Hospital Register and the Danish Cancer Registry.ResultsWe identified 991,454 (78%) children from core families with 53,995 children who had a full sibling with a CM and 277,773 (22%) children from broken families with 7200 children who had a full sibling with a CM and 6194 children who had a half sibling with a CM. Children who had a full sibling with a CM from both core and broken families showed, in general, no increased cancer risk compared with children whose siblings had no CM, except in the case of children who had a full sibling with a CM in the nervous system (HR=2.61, 95%CI:1.60–4.27) or in the eye, ear, face, or neck (HR=2.47, 95%CI: 1.46–4.18). Children who had a half sibling with a CM seemed to have a higher cancer risk in early adulthood (HR=1.87, 95%CI: 0.98–3.56).ConclusionsChildren who had a full sibling with a CM had no increased risk of cancer except for those who had a full sibling with a CM in the nervous system or in the eye, ear, face or neck. Children with a half-sibling with a CM tended to have an increased cancer risk in early adulthood, perhaps a result of chance. This study should be replicated using other data sources.



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Abdomen/pelvis computed tomography in staging of pediatric Hodgkin Lymphoma: is it always necessary?

Abstract

The purpose of the study was to determine if abdomen/pelvis computed tomography (CT) can be safety omitted in the initial staging of a subgroup of children affected by Hodgkin Lymphoma (HL). Every participating center of A.I.E.O.P (Associazione Italiana di Ematologia ed Oncologia Pediatrica) sent local staging reports of 18F-fluorodeoxyglucose positron emission tomography (PET) and abdominal ultrasound (US) along with digital images of staging abdomen/pelvis CT to the investigation center where the CT scans were evaluated by an experienced pediatric radiologist. The local radiologist who performed the US was unaware of local CT and PET reports (both carried out after US), and the reviewer radiologist examining the CT images was unaware of local US, PET and CT reports. A new abdominal staging of 123 patients performed on the basis of local US report, local PET report, and centralized CT report was then compared to a simpler staging based on local US and PET. No additional lesion was discovered by CT in patients with abdomen/pelvis negativity in both US and PET or isolated spleen positivity in US (or US and PET), and so it seems that in the initial staging, abdomen/pelvis CT can be safety omitted in about 1/2 to 2/3 of children diagnosed with HL.

We decided to verify if there was an overadministration of staging computed tomography (CT) in pediatric HL. A new staging of 123 patients performed on the basis of local US report, local PET report, and centralized CT report was compared to a simpler staging based on local US and PET. No additional lesion was discovered by CT in patients with abdomen/pelvis negativity in both US and PET or isolated spleen positivity in US (or US and PET).

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Clinicopathological feature and prognosis of primary hepatic gastrointestinal stromal tumor

Abstract

Compared to gastric gastrointestinal stromal tumor (GIST), hepatic GIST is very rare in clinic. Reports on clinicopathological feature and prognosis of this rare disease are limited in literature. The purpose of this study was, therefore, to summarize clinical and pathological features as well as prognosis of the primary hepatic GIST. One case of primary hepatic GIST from our center and 22 cases reported in MEDLINE or China National Knowledge Infrastructure (CNKI) were enrolled into this study. Clinicopathological features as well as survival data of hepatic GIST were analyzed and compared with 297 gastric GISTs and 59 small intestinal GISTs from our center. Majority of the 22 cases (95.7%) of hepatic GIST was larger than 5 cm in size, and 75.0% of the tumors were over 5/50 HPF in mitotic index. Most of the hepatic GISTs (85.7%) displayed spindle cell shape in morphology. All of the hepatic GIST (100%) enrolled in this study were classified as high-risk category by the National Institute of Health (NIH) risk classification. The 5-year median disease-free survival (DFS) time was 24.0 months and 5-year disease-specific survival (DSS) rate was 33.3%, respectively. Distribution of clinicopathological features was significantly different among hepatic, gastric, and small intestinal GIST. The DFS and DSS of hepatic GIST were significantly lower than those of the other two groups. Majority of the hepatic GIST is large in size and highly malignant. Prognosis of the primary hepatic GIST is worse than that of gastric GIST and small intestinal GIST.

Clinicopathological features and prognosis of hepatic gastrointestinal stromal tumor (GIST)s are limited due to the extremely rare incidence. This study indicated that majority of the hepatic GIST is large in size and highly malignant. Prognosis of the primary hepatic GIST is worse than that of gastric and small intestinal GIST.

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Dual pharmacological inhibition of glutathione and thioredoxin systems synergizes to kill colorectal carcinoma stem cells

Abstract

NRF2 stabilizes redox potential through genes for glutathione and thioredoxin antioxidant systems. Whether blockade of glutathione and thioredoxin is useful in eliminating cancer stem cells remain unknown. We used xenografts derived from colorectal carcinoma patients to investigate the pharmacological inhibition of glutathione and thioredoxin systems. Higher expression of five glutathione S-transferase isoforms (GSTA1, A2, M4, O2, and P1) was observed in xenograft-derived spheroids than in fibroblasts. Piperlongumine (2.5–10 μmol/L) and auranofin (0.25–4 μmol/L) were used to inhibit glutathione S-transferase π and thioredoxin reductase, respectively. Piperlongumine or auranofin alone up-regulated the expression of NRF2 target genes, but not TP53 targets. While piperlongumine showed modest cancer-specific cell killing (IC₅₀ difference between cancer spheroids and fibroblasts: P = 0.052), auranofin appeared more toxic to fibroblasts (IC₅₀ difference between cancer spheroids and fibroblasts: P = 0.002). The synergism of dual inhibition was evaluated by determining the Combination Index, based on the number of surviving cells with combination treatments. Molar ratios indicated synergism in cancer spheroids, but not in fibroblasts: (auranofin:piperlongumine) = 2:5, 1:5, 1:10, and 1:20. Cancer-specific cell killing was achieved at the following drug concentrations (auranofin:piperlongumine): 0.25:2.5 μmol/L, 0.5:2.5 μmol/L, or 0.25:5 μmol/L. The dual inhibition successfully decreased CD44v9 surface presentation and delayed tumor emergence in nude mouse. However, a small subpopulation persistently survived and accumulated phosphorylated histone H2A. Such "persisters" still retained lesser but significant tumorigenicity. Thus, dual inhibition of glutathione S-transferase π and thioredoxin reductase could be a feasible option for decreasing the tumor mass and CD44v9-positive fraction by disrupting redox regulation.

Glutathione and thioredoxin systems contribute to reduction of reactive oxygen species. Both antioxidant peptides are recycled by reducing power of NADPH, mostly produced in pentose phosphate pathway. We have shown that single inhibition of either glutathione or thioredoxin compensate the other systems by transcription factor NRF2. Dual inhibition of glutathione and thioredoxin displayed synergistic cell killing against colorectal carcinoma-derived cancer spheroids.

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PRDM5 promotes the proliferation and invasion of murine melanoma cells through up-regulating JNK expression

Abstract

PRDM (PRDI-BF1 and RIZ domain-containing) proteins constitute a family of zinc finger proteins and play important roles in multiple cellular processes by acting as epigenetic modifiers. PRDM5 is a recently identified member of the PRDM family and may function as a tumor suppressor in several types of cancer. However, the role of PRDM5 in murine melanoma remains largely unknown. In our study, effect of PRDM5 on murine melanoma cells was determined and results showed that PRDM5 overexpression significantly promoted proliferation, migration, and invasion of murine melanoma B16F10 cells. Consistently, silencing of PRDM5 expression significantly inhibited proliferation, invasion, and migration of B16F10 cells. In vivo study also showed that PRDM5 silencing significantly inhibited the growth and metastasis of melanoma in mice. PRDM5 was then found to increase the expression and activation of JNK in B16F10 cells. JNK silencing significantly reduced PRDM5-mediated up-regulation of JNK expression and blocked the PRDM5-induced proliferation and invasion of B16F10 cells. To further verify the involvement of JNK signaling in PRDM5-induced progression of B16F10 cells, a specific JNK inhibitor was employed to inhibit the JNK signaling pathway, and results showed that PRDM5-induced proliferation and invasion of B16F10 cells were abolished. We conclude that PRDM5 promotes the proliferation and invasion of murine melanoma cells through up-regulating JNK expression and strategies targeting PRDM5 may be promising for the therapy of melanoma.

We conclude that PRDM5 promotes the proliferation and invasion of murine melanoma cells through up-regulating JNK expression. Our findings suggest that strategies targeting PRDM5 may be promising for the therapy of melanoma.

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Association between targeted somatic mutation (TSM) signatures and HGS-OvCa progression

Abstract

Evidence already exists that the activation-induced cytidine deaminase (AID/APOBEC) and the adenosine deaminase (ADAR) families of enzymes are implicated as powerful mutagens in oncogenic processes in many somatic tissues. Each deaminase is identified by the DNA or RNA nucleotide sequence ("motif") surrounding the nucleotide targeted for deamination. The primary objective of this study is to develop an in silico approach to identify nucleotide sequence changes of the target motifs of key deaminases during oncogenesis. If successful, a secondary objective is to investigate if such changes are associated with disease progression indicators that include disease stage and progression-free survival time. Using a discovery cohort of 194 high-grade serous ovarian adenocarcinoma (HGS-OvCa) exomes, the results confirm the ability of the novel in silico approach used to identify changes in the preferred target motifs for AID, APOBEC3G, APOBEC3B, and ADAR1 during oncogenesis. Using this approach, a set of new cancer-progression associated signatures (C-PASs) were identified. Furthermore, it was found that the C-PAS identified can be used to differentiate between the cohort of patients that remained progression-free for longer than 60 months, from those in which disease progressed within 60 months (sensitivity 95%, specificity 90%). The spectrum of outcomes observed here could provide a foundation for future clinical assessment of susceptibility variants in ovarian, and several other cancers as disease progresses. The ability of the in silico methodology used to identify changes in deaminase motifs during oncogenesis also suggests new links between immune system function and tumorigenesis.

The aim of our study was to use a new bioinformatics approach to identify genetic signature changes that occur during oncogenesis. Using 194 TCGA GHGS-OvCa samples, we identified a set of genetic signatures that might be adapted for use as a genetic assay to predict the progression-free survival probability within 60 months following the initial diagnosis (sensitivity 95%, specificity 90%).

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Noninvasive early detection of anthracycline-induced cardiotoxicity in patients with hematologic malignancies using the phased tracking method

Abstract

Anthracyclines are among the most effective and widely used anticancer drugs; however, their use is limited by serious cardiotoxicity. Early detection is necessary to prevent the high mortality rate associated with heart failure (HF). We evaluated cardiac function in 142 patients using conventional echocardiography and the phased tracking method (PTM), which was measured using the minute vibration and the rapid motion components, neither of which is recognized in standard M-mode nor in tissue Doppler imaging. For systolic function comparison, we compared left ventricular ejection fraction (LVEF) in conventional echocardiography with the average velocity of ventricular septum myocytes (V_ave) in the PTM. The V_ave of 12 healthy volunteers was 1.5 (m/s)/m or more. At baseline of 99 patients, there was a positive correlation between LVEF and V_ave in all patients. There were no significant differences in baseline cardiac function between patients with and without HF. There was a negative correlation between the cumulative anthracycline dose and LVEF or V_ave among all patients. We determined that V_ave 1.5 (m/s)/m was equivalent to LVEF 60%, 1.25 (m/s)/m to 55%, and 1.0 (m/s)/m to 50%. During the follow-up period, there was a pathological decrease in LVEF (<55%) and V_ave (<1.25 m/s/m) in patients with HF; decreases in V_ave were detected significantly earlier than those in LVEF (P < 0.001). When V_ave declined to 1.5 (m/s)/m or less, careful continuous observation and cardiac examination was required. When V_ave further declined to 1.0 (m/s)/m or lower, chemotherapy was postponed or discontinued; thus, serious drug-induced cardiomyopathy was avoided in patients who did not relapse. The PTM was superior to echocardiography for early, noninvasive detection and intermediate-term monitoring of left ventricle systolic function associated with anthracycline chemotherapy, among patients with hematologic malignancies. The PTM was an effective laboratory procedure to avoid the progression to serious cardiomyopathy.

The phased tracking method; a high-resolution Doppler measurement is noninvasive detected laboratory procedure that may help avoid progression to serious cardiomyopathy.

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An analysis of the relationship between metastases and cachexia in lung cancer patients

Abstract

Weight loss and hematogenous metastases are poor prognosis factors in lung cancer patients that can but do not necessarily co-occur. We retrospectively investigated the clinical association between cachexia, tumor characteristics (such as metastatic burden and mutational status), and treatment in lung cancer patients. The medical records of 394 lung cancer patients from two institutions (Columbia University, USA and Tohoku University, Japan) were reviewed. Information collected included the presence of cachexia, histologic subtype, tumor stage, number of metastases, mutation status, treatment, and survival. Descriptive statistics were performed. Only stage IV patients exhibited >5% weight loss (0.8%, 2.2%, 3.6%, and 5.1%, for stages I to IV; P = 0.0001). Patients with metastases developed cachexia more often than patients without metastases independent of treatment (6.0% and 7.1% weight loss in patients with metastases vs. 2.5% and 2.0% in patients without metastases, before [P = 0.0001] and after [P < 0.0001] treatment, respectively). The change in number of metastatic sites over time correlated with increasing weight loss (5.2%, 10.6%, 13.4%, and 13.4%, for an increase of 0, 1, 2, and ≥3 metastatic sites, from initial diagnosis to the endpoint; P < 0.0001). Patients with cachexia had worse survival than patients without cachexia (hazard ratio, 2.94; 95% confidence interval, 2.08–4.16; P < 0.0001). Tumors with mutated KRAS were associated with an increased risk of weight loss (11.4% weight loss in patients with mutated KRAS vs. 6.0% in patients with wild-type KRAS; P = 0.0011). Our findings suggest that the capabilities of lung cancer to metastasize and cause cachexia might be linked intrinsically and are independent of treatments administered. KRAS-mutated tumors were more commonly associated with cachexia.

We retrospectively investigated the clinical association between cachexia, tumor characteristics (such as metastatic burden and mutational status), and treatment in lung cancer patients. Our findings suggest that the capabilities of lung cancer to metastasize and cause cachexia might be linked intrinsically and are independent of treatments administered. KRAS-mutated tumors are more commonly associated with cachexia.

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Impact of aerobic exercise on levels of IL-4 and IL-10: results from two randomized intervention trials

Abstract

The mechanisms whereby regular exercise reduces chronic inflammation remain unclear. We investigated whether regular aerobic exercise alters basal levels of interleukin (IL)-10 and IL-4 in two randomized trials of physical activity. The Alberta Physical Activity and Breast Cancer Prevention Trial (ALPHA, n = 320) and the Breast Cancer and Exercise Trial in Alberta (BETA, n = 400) were two-center, two-armed randomized trials in inactive, healthy, postmenopausal women. Both trials included an exercise intervention prescribed five times/week and no dietary changes. In ALPHA, the exercise group was prescribed 225 min/week versus no activity in the controls. BETA examined dose-response effects comparing 300 (HIGH) versus 150 (MODERATE) min/week. Plasma concentrations of IL-10 and IL-4 were measured at baseline, 6, and 12 months. Intention-to-treat (ITT) analysis was performed using linear mixed models adjusted for baseline biomarker concentrations. Circulating anti-inflammatory cytokine levels decreased among all groups, with percent change ranging from −3.4% (controls) to −8.2% (HIGH) for IL-4 and −1.6% (controls) to −7.5% (HIGH) for IL-10. No significant group differences were found for IL-4 (ALPHA P = 0.54; BETA P = 0.32) or IL-10 (ALPHA P = 0.84; BETA P = 0.68). Some evidence for moderation of the effect of exercise by baseline characteristics was found for IL-10 but not for IL-4. Results from these two large randomized aerobic exercise intervention trials suggest that aerobic exercise does not alter IL-10 or IL-4 in a manner consistent with chronic disease and cancer prevention.

The mechanisms whereby regular exercise reduces chronic inflammation remain unclear. We investigated whether regular aerobic exercise alters basal levels of interleukin (IL)-10 and IL-4 in two randomized trials of physical activity. Results from these two large randomized aerobic exercise intervention trials suggest that aerobic exercise does not alter IL-10 or IL-4 in a manner consistent with chronic disease and cancer prevention.

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Ultrasound imaging of splenomegaly as a proxy to monitor colon tumor development in Apcmin716/+ mice

Abstract

Animal models of colon cancer are widely used to understand the molecular mechanisms and pathogenesis of the disease. These animal models require a substantial investment of time and traditionally necessitate the killing of the animal to measure the tumor progression. Several in vivo imaging techniques are being used in both human clinics and preclinical studies, albeit at high cost and requiring particular expertise. Here, we report that the progression of splenomegaly coincides with and positively correlates to colon tumor development in Apc^min716/+ mice expressing a mutant gene encoding an adenomatous polyposis coli protein truncated at amino acid 716. Ultrasound image-based spleen size measurement precisely mirrors splenomegaly development in vivo in the tumor-laden Apc^min716/+ mice. Moreover, the spleen dimensions extracted from the ultrasound sonograms are positively correlated with normalized spleen weight and the number and area of colon tumors. Hence, we propose measuring the spleen size in vivo by ultrasound imaging as a novel approach to estimate splenomegaly development and to indirectly monitor colon tumor development in Apc^min716/+ mice. The widespread use of ultrasound machines in the laboratory setting, coupled with the fact that it is a noninvasive method, make it a straightforward and useful tool for monitoring the experimental progress of colon cancer in mice and determining end points without killing animals strictly for diagnostics purposes.

The relationship between colon tumorigenesis and splenomegaly in Apc^Min/+ mice has not been investigated. We demonstrate that splenomegaly progression coincides with and positively correlates to colon tumor development in Apc^min716/+ mice and ultrasound image-based spleen measurement precisely monitors splenomegaly development in vivo. These findings reveal measuring the spleen size in vivo by ultrasound imaging is a novel noninvasive approach to estimate splenomegaly development as an indirect monitoring tool for colon tumor development in Apc^min716/+ mice.

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Proteomic analysis of differentially expressed proteins in vitreous humor of patients with retinoblastoma using iTRAQ-coupled ESI-MS/MS approach

Abstract

There is close proximity of vitreous humor with the tumor bulk in eyes with retinoblastoma. This renders vitreous humor a promising source to evaluate disease-specific protein targets in retinoblastoma. We studied the differential proteome of vitreous fluid in retinoblastoma tumors (n = 4) as compared to controls (n = 4). The vitreous humor was depleted off the high abundant fraction using MARS-6 affinity column. Subsequently, the tryptic peptides were derivatised with iTRAQ labels. The labelled peptides were pooled and subjected to fractionation using bRPLC. This was followed by protein identification and quantification using electrospray ionisation mass spectrometry (ESI-MS/MS) approach. The identified proteins were subjected to bioinformatics analysis utilizing PANTHER 7.0 and IPA software. Four hundred and thirty-one non-redundant (362 upregulated and 69 downregulated) proteins (≥2 unique peptides, ± 1.5 folds, p < 0.05) were identified. The majority of the proteins were cytoplasmic (40 %), majorly involved in catalytic (32.7 %) and binding activities (26.3 %). Highly deregulated proteins included MMP2, TNC, CD44, SUZ12 and CRABP1. The protein expression of GFAP, CRABP1, MMP2 and TNC was validated by western blotting. Pathway and network analyses revealed p38MAPK and Akt signalling to be the most significantly regulated pathways in retinoblastoma. This is the first report of differential vitreous proteome of retinoblastoma and highlights novel protein targets, such as MMP2, TNC and CRABP1. Further investigations into unravelling the biological role of the proteins and their prospects of being utilised as potential candidates in therapeutics are warranted.

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Tumor suppressor Fbxw7 antagonizes WNT signaling by targeting β-catenin for degradation in pancreatic cancer

Abstract

Pancreatic cancer is one of the deadliest solid malignancies associated with aberrant Wnt signaling activation. Fbxw7 mutations have been implicated in the development of pancreatic cancer, whereas the exact mechanism of this ubiquitin ligase as a tumor suppressor remains unclear in pancreatic carcinogenesis. Here, we describe that Fbxw7 is downregulated upon pancreatic cancer development. Depletion of Fbxw7 results in tumor suppression in pancreatic cancer cells, while Fbxw7 overexpression inhibits pancreatic cancer cell proliferation and invasion. Considering the negative correlation between Fbxw7 and β-catenin, we find that Fbxw7 antagonizes Wnt signaling through targeting β-catenin for its degradation. Moreover, the inhibitory effect of Fbxw7 on pancreatic cancer cell proliferation is mainly executed by the destruction of the Wnt/β-catenin signaling pathway. We also reveal that c-myc, a widely accepted target of Fbxw7, is also transcriptionally regulated by the Fbxw7/β-catenin axis in pancreatic cancer cells. Collectively, our results demonstrate that Fbxw7 is a novel regulator of Wnt/β-catenin signaling-dependent regulation of pancreatic cancer cell growth and invasion, and inactivation of Fbxw7 in pancreatic cancer tissues might be the reason for the aberrant activation of Wnt signaling.

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Cytosolic Ku70 regulates Bax-mediated cell death

Abstract

The first known function of Ku70 is as a DNA repair factor in the nucleus. Using neuronal neuroblastoma cells as a model, we have established that cytosolic Ku70 binds to the pro-apoptotic protein Bax in the cytosol and blocks Bax's cell death activity. Ku70-Bax binding is regulated by Ku70 acetylation in that when Ku70 is acetylated Bax dissociates from Ku70, triggering cell death. We propose that Ku70 may act as a survival factor in these cells such that Ku70 depletion triggers Bax-dependent cell death. Here, we addressed two fundamental questions about this model: (1) Does all Bax, which is a cytosolic protein, bind to all cytosolic Ku70? and (2) Is Ku70 a survival factor in cells types other than neuronal neuroblastoma cells? We show here that, in neuronal neuroblastoma cells, only a small fraction of Ku70 binds to a small fraction of Bax; most Bax is monomeric. Interestingly, there is no free or monomeric Ku70 in the cytosol; most cytosolic Ku70 is in complex with other factors forming several high molecular weight complexes. A fraction of cytosolic Ku70 also binds to cytosolic Ku80, Ku70's binding partner in the nucleus. Ku70 may not be a survival factor in some cell types (Ku70-depletion less sensitive) because Ku70 depletion does not affect survival of these cells. These results indicate that, in addition to Ku70 acetylation, other factors may be involved in regulating Ku70-Bax binding in the Ku70-depletion less sensitive cells because Ku70 acetylation in these cells is not sufficient to dissociate Bax from Ku70 or to activate Bax.

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IQGAP1 gene silencing induces apoptosis and decreases the invasive capacity of human hepatocellular carcinoma cells

Abstract

IQ motif-containing GTPase-activating proteins (IQGAPs) belong to a conserved family, and they are involved in various intracellular processes. IQGAP1 is expressed in all cells, while IQGAP2 and IQGAP3 are mainly expressed in hepatic cells. IQGAP1 has been suggested to be an oncogene, while IQGAP2 is considered a tumor-suppressor gene. However, the relationship between RAS family genes and IQGAP genes remains unclear. We recently demonstrated this interaction in a chemically induced mouse liver cancer. In this study, IQGAP1 expression was partially silenced in human hepatocellular carcinoma (HepG2) cells. We investigated the impact of IQGAP1 silencing on the interactions of IQGAP and RAS with several apoptotic proteins, including caspase-3 (CASP3), BCL2-associated X protein (BAX), and B-cell leukemia/lymphoma 2 (BCL2). Additionally, we investigated the effects of the interactions of these genes on cell viability, proliferation, apoptosis, and invasive capacity. IQGAP1 siRNA-treated HepG2 cells showed lower invasive capacity than the control cells, and this reduction was time- and vector concentration-dependent. In addition, IQGAP1 silencing resulted in significantly lower IQGAP1 level and subsequently higher IQGAP2 and IQGAP3 expression in HepG2 cells than in the control. Flow cytometry analyses indicated that the silencing of IQGAP1 can induce early and late apoptosis in HepG2 cells. Additionally, IQGAP2, IQGAP3, CASP3, and BAX were upregulated whereas IQGAP1 and BCL2 were downregulated in the siRNA-treated cells. Furthermore, we observed that the mRNA levels of HRAS, KRAS, NRAS, and MRAS decreased upon IQGAP1 silencing. These findings indicate that IQGAP1 potentially regulates the expression of IQGAP and RAS gene families and demonstrate its regulatory role in the apoptotic network. Taken together, our findings suggest that IQGAP1 silencing plays crucial roles in the apoptosis of HepG2 cells and lowers their proliferative and invasive capacities.

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Clinical significance of β2-adrenergic receptor expression in patients with surgically resected gastric adenocarcinoma

Abstract

The β2-adrenergic receptor (β2-AR) is highly expressed in various human neoplasms and has been considered a novel therapeutic target of cancer treatment. However, the clinicopathological significance of β2-AR expression in patients with gastric cancer (GC) remains unclear. The aim of this study was to explore β2-AR expression and its prognostic significance. A total of 331 patients with surgically resected GC were evaluated. Tumor sections were stained immunohistochemically for β2-AR. And, we confirmed β2-AR expression in the GC cell lines by Western blot. β2-AR was highly expressed in 30.5 % of GC patients. Expression was significantly associated with age, T factor, tumor differentiation, histology of non-signet cells, lymphatic permeation, and vascular invasion. And, all the GC cell lines expressed β2-AR. On univariate analysis, age, disease stage, T factor, N factor, lymphatic permeation, vascular invasion, and β2-AR expression were significantly associated with overall survival. Although the multivariate analysis did not indicate that β2-AR expression was independently prognostic of survival, high-level β2-AR expression was associated with significantly poorer survival of GC patients with well or moderately differentiated tumors. β2-AR expression was a significant predictor of tumor aggressiveness in, and poorer survival of, patients with GC.

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Proteomic analysis of differentially expressed proteins in vitreous humor of patients with retinoblastoma using iTRAQ-coupled ESI-MS/MS approach

Abstract

There is close proximity of vitreous humor with the tumor bulk in eyes with retinoblastoma. This renders vitreous humor a promising source to evaluate disease-specific protein targets in retinoblastoma. We studied the differential proteome of vitreous fluid in retinoblastoma tumors (n = 4) as compared to controls (n = 4). The vitreous humor was depleted off the high abundant fraction using MARS-6 affinity column. Subsequently, the tryptic peptides were derivatised with iTRAQ labels. The labelled peptides were pooled and subjected to fractionation using bRPLC. This was followed by protein identification and quantification using electrospray ionisation mass spectrometry (ESI-MS/MS) approach. The identified proteins were subjected to bioinformatics analysis utilizing PANTHER 7.0 and IPA software. Four hundred and thirty-one non-redundant (362 upregulated and 69 downregulated) proteins (≥2 unique peptides, ± 1.5 folds, p < 0.05) were identified. The majority of the proteins were cytoplasmic (40 %), majorly involved in catalytic (32.7 %) and binding activities (26.3 %). Highly deregulated proteins included MMP2, TNC, CD44, SUZ12 and CRABP1. The protein expression of GFAP, CRABP1, MMP2 and TNC was validated by western blotting. Pathway and network analyses revealed p38MAPK and Akt signalling to be the most significantly regulated pathways in retinoblastoma. This is the first report of differential vitreous proteome of retinoblastoma and highlights novel protein targets, such as MMP2, TNC and CRABP1. Further investigations into unravelling the biological role of the proteins and their prospects of being utilised as potential candidates in therapeutics are warranted.

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Tumor suppressor Fbxw7 antagonizes WNT signaling by targeting β-catenin for degradation in pancreatic cancer

Abstract

Pancreatic cancer is one of the deadliest solid malignancies associated with aberrant Wnt signaling activation. Fbxw7 mutations have been implicated in the development of pancreatic cancer, whereas the exact mechanism of this ubiquitin ligase as a tumor suppressor remains unclear in pancreatic carcinogenesis. Here, we describe that Fbxw7 is downregulated upon pancreatic cancer development. Depletion of Fbxw7 results in tumor suppression in pancreatic cancer cells, while Fbxw7 overexpression inhibits pancreatic cancer cell proliferation and invasion. Considering the negative correlation between Fbxw7 and β-catenin, we find that Fbxw7 antagonizes Wnt signaling through targeting β-catenin for its degradation. Moreover, the inhibitory effect of Fbxw7 on pancreatic cancer cell proliferation is mainly executed by the destruction of the Wnt/β-catenin signaling pathway. We also reveal that c-myc, a widely accepted target of Fbxw7, is also transcriptionally regulated by the Fbxw7/β-catenin axis in pancreatic cancer cells. Collectively, our results demonstrate that Fbxw7 is a novel regulator of Wnt/β-catenin signaling-dependent regulation of pancreatic cancer cell growth and invasion, and inactivation of Fbxw7 in pancreatic cancer tissues might be the reason for the aberrant activation of Wnt signaling.

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Cytosolic Ku70 regulates Bax-mediated cell death

Abstract

The first known function of Ku70 is as a DNA repair factor in the nucleus. Using neuronal neuroblastoma cells as a model, we have established that cytosolic Ku70 binds to the pro-apoptotic protein Bax in the cytosol and blocks Bax's cell death activity. Ku70-Bax binding is regulated by Ku70 acetylation in that when Ku70 is acetylated Bax dissociates from Ku70, triggering cell death. We propose that Ku70 may act as a survival factor in these cells such that Ku70 depletion triggers Bax-dependent cell death. Here, we addressed two fundamental questions about this model: (1) Does all Bax, which is a cytosolic protein, bind to all cytosolic Ku70? and (2) Is Ku70 a survival factor in cells types other than neuronal neuroblastoma cells? We show here that, in neuronal neuroblastoma cells, only a small fraction of Ku70 binds to a small fraction of Bax; most Bax is monomeric. Interestingly, there is no free or monomeric Ku70 in the cytosol; most cytosolic Ku70 is in complex with other factors forming several high molecular weight complexes. A fraction of cytosolic Ku70 also binds to cytosolic Ku80, Ku70's binding partner in the nucleus. Ku70 may not be a survival factor in some cell types (Ku70-depletion less sensitive) because Ku70 depletion does not affect survival of these cells. These results indicate that, in addition to Ku70 acetylation, other factors may be involved in regulating Ku70-Bax binding in the Ku70-depletion less sensitive cells because Ku70 acetylation in these cells is not sufficient to dissociate Bax from Ku70 or to activate Bax.

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IQGAP1 gene silencing induces apoptosis and decreases the invasive capacity of human hepatocellular carcinoma cells

Abstract

IQ motif-containing GTPase-activating proteins (IQGAPs) belong to a conserved family, and they are involved in various intracellular processes. IQGAP1 is expressed in all cells, while IQGAP2 and IQGAP3 are mainly expressed in hepatic cells. IQGAP1 has been suggested to be an oncogene, while IQGAP2 is considered a tumor-suppressor gene. However, the relationship between RAS family genes and IQGAP genes remains unclear. We recently demonstrated this interaction in a chemically induced mouse liver cancer. In this study, IQGAP1 expression was partially silenced in human hepatocellular carcinoma (HepG2) cells. We investigated the impact of IQGAP1 silencing on the interactions of IQGAP and RAS with several apoptotic proteins, including caspase-3 (CASP3), BCL2-associated X protein (BAX), and B-cell leukemia/lymphoma 2 (BCL2). Additionally, we investigated the effects of the interactions of these genes on cell viability, proliferation, apoptosis, and invasive capacity. IQGAP1 siRNA-treated HepG2 cells showed lower invasive capacity than the control cells, and this reduction was time- and vector concentration-dependent. In addition, IQGAP1 silencing resulted in significantly lower IQGAP1 level and subsequently higher IQGAP2 and IQGAP3 expression in HepG2 cells than in the control. Flow cytometry analyses indicated that the silencing of IQGAP1 can induce early and late apoptosis in HepG2 cells. Additionally, IQGAP2, IQGAP3, CASP3, and BAX were upregulated whereas IQGAP1 and BCL2 were downregulated in the siRNA-treated cells. Furthermore, we observed that the mRNA levels of HRAS, KRAS, NRAS, and MRAS decreased upon IQGAP1 silencing. These findings indicate that IQGAP1 potentially regulates the expression of IQGAP and RAS gene families and demonstrate its regulatory role in the apoptotic network. Taken together, our findings suggest that IQGAP1 silencing plays crucial roles in the apoptosis of HepG2 cells and lowers their proliferative and invasive capacities.

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Clinical significance of β2-adrenergic receptor expression in patients with surgically resected gastric adenocarcinoma

Abstract

The β2-adrenergic receptor (β2-AR) is highly expressed in various human neoplasms and has been considered a novel therapeutic target of cancer treatment. However, the clinicopathological significance of β2-AR expression in patients with gastric cancer (GC) remains unclear. The aim of this study was to explore β2-AR expression and its prognostic significance. A total of 331 patients with surgically resected GC were evaluated. Tumor sections were stained immunohistochemically for β2-AR. And, we confirmed β2-AR expression in the GC cell lines by Western blot. β2-AR was highly expressed in 30.5 % of GC patients. Expression was significantly associated with age, T factor, tumor differentiation, histology of non-signet cells, lymphatic permeation, and vascular invasion. And, all the GC cell lines expressed β2-AR. On univariate analysis, age, disease stage, T factor, N factor, lymphatic permeation, vascular invasion, and β2-AR expression were significantly associated with overall survival. Although the multivariate analysis did not indicate that β2-AR expression was independently prognostic of survival, high-level β2-AR expression was associated with significantly poorer survival of GC patients with well or moderately differentiated tumors. β2-AR expression was a significant predictor of tumor aggressiveness in, and poorer survival of, patients with GC.

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DNA damage after chronic oxytocin administration in rats: a safety yellow light?

Abstract

Adjuvant therapy is a common therapeutic strategy used for schizophrenia management. Oxytocin has shown promising results as antipsychotic adjuvant in patients with schizophrenia. Although short-term clinical studies have indicated tolerability and no major side-effect manifestation, long-term studies remain needed. In this study, we investigated whether oxytocin chronic administration in rats may lead to brain DNA damage by comet assay. Our results suggest that 21 and 56-day treatment with once daily intraperitoneal oxytocin (0.1, 1.0 and 10.0 mg/kg) may cause substantial DNA damage in hippocampus. We have not found differences on body weight gain. Our findings also point that further clinical and preclinical studies evaluating oxytocin safety after chronic exposure are necessary.

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SB203580 reverses memory deficits and depression-like behavior induced by microinjection of Aβ 1–42 into hippocampus of mice

Abstract

A high co-morbidity between Alzheimer's disease (AD) and depression suggests there might be similar mechanisms underlying the course of these diseases. Previous studies have shown that p38MAPK plays a critical role in the pathophysiology of AD and depression. However, little is known about whether SB203580, a selective inhibitor of p38MAPK, may protect against AD-associated cognitive impairments and depression-like behavior, simultaneously. Herein, we have shown, for the first time, that SB203580 may reverse memory impairments and depression-like behavior induced by hippocampal infusion of β-amyloid 1–42 (Aβ_1–42), as measured by novel object recognition, Morris water maze, tail-suspension and forced-swimming tests. In addition, phorbol 12-myristate 13-acetate (PMA), a PKC activator which also activates p38MAPK, significantly abolished the effects of SB203580. Moreover, Aβ_1–42 causes increased phosphorylation of p38MAPK and decreased phosphorylation of Ser9-glycogen synthase kinase 3β (GSK3β) and cAMP-response element binding protein (CREB) in the hippocampus of mice, which could be significantly reversed by SB203580. Our results suggest that SB203580 reversed Aβ_1–42-induced cognitive impairments and depression-like behavior via inhibiting p38MAPK signaling pathway, which not only supports p38MAPK as a therapeutic target for AD-associated cognitive dysfunction and depression-like behavior, but also provides experimental basis for the use of SB203580 in co-morbidity of AD and depression.

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Neuroprotective effect of Cucumis melo Var. flexuosus leaf extract on the brains of rats with streptozotocin-induced diabetes

Abstract

The central nervous system is one of the most vulnerable organs affected by the oxidative stress associated with diabetes mellitus. Healthy food provides an important source for antioxidants. Therefore, the protective effect of Cucumis melo var. flexuosus (C. melo var. flexuosus) leaf extract on the brains of diabetic rats was investigated. Adult male albino rats divided into 5 groups of 6 rats each were assigned into a normal control group and four diabetic groups. Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin (STZ; 60 mg/kg bw). One of the four diabetic groups was left untreated and was considered as a diabetic control group while the three other groups were treated with C. melo var. flexuosus leaf extract at the doses of 30, 60 and 120 mg/kg bw for a period of 30 days. After completion of experimental duration plasma and brains were used for evaluating biochemical changes. The obtained data showed that C. melo var. flexuosus leaf extract treatment lowered blood glucose, glycated hemoglobin, brain tumor necrosis factor-alpha, interleukin levels, brain malondialdehyde content and caspase-3 activity. Furthermore, the treatment resulted in a marked increase in plasma dopamine, melatonin, brain vascular endothelial growth factor-A levels, brain catalase and superoxide dismutase activities. From the present study, it can be concluded that the C. melo var. flexuosus leaf extract exerts a neuroprotective effect against oxidative damage associated with diabetes.

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Chemotherapy and radiation therapy elicits tumor specific T cell responses in a breast cancer patient

Abstract

Background

Experimental evidence and clinical studies in breast cancer suggest that some anti-tumor therapy regimens generate stimulation of the immune system that accounts for tumor clinical responses, however, demonstration of the immunostimulatory power of these therapies on cancer patients continues to be a formidable challenge. Here we present experimental evidence from a breast cancer patient with complete clinical response after 7 years, associated with responsiveness of tumor specific T cells.

Methods

T cells were obtained before and after anti-tumor therapy from peripheral blood of a 63-years old woman diagnosed with ductal breast cancer (HER2/neu+++, ER-, PR-, HLA-A*02:01) treated with surgery, followed by paclitaxel, trastuzumab (suspended due to cardiac toxicity), and radiotherapy. We obtained a leukapheresis before surgery and after 8 months of treatment. Using in vitro cell cultures stimulated with autologous monocyte-derived dendritic cells (DCs) that produce high levels of IL-12, we characterize by flow cytometry the phenotype of tumor associated antigens (TAAs) HER2/neu and NY-ESO 1 specific T cells. The ex vivo analysis of the TCR-Vβ repertoire of TAA specific T cells in blood and Tumor Infiltrating Lymphocytes (TILs) were performed in order to correlate both repertoires prior and after therapy.

Results

We evidence a functional recovery of T cell responsiveness to polyclonal stimuli and expansion of TAAs specific CD8+ T cells using peptide pulsed DCs, with an increase of CTLA-4 and memory effector phenotype after anti-tumor therapy. The ex vivo analysis of the TCR-Vβ repertoire of TAA specific T cells in blood and TILs showed that whereas the TCR-Vβ04-02 clonotype is highly expressed in TILs the HER2/neu specific T cells are expressed mainly in blood after therapy, suggesting that this particular TCR was selectively enriched in blood after anti-tumor therapy.

Conclusions

Our results show the benefits of anti-tumor therapy in a breast cancer patient with clinical complete response in two ways, by restoring the responsiveness of T cells by increasing the frequency and activation in peripheral blood of tumor specific T cells present in the tumor before therapy.

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