bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P2-02-03: HER2 expression on circulating tumor cells before adjuvant chemotherapy and during follow-up in patients with HER2-negative early breast cancer
Authors: Markomanolaki H , Mavroudis D , Kallergi G , Vetsika E-K , Stratigos M , Makrigiannaki K , Georgoulias V , Agelaki S
Published: May 2016

Background: Detection of circulating tumor cells (CTCs) before adjuvant chemotherapy as well as during follow-up is related to poor prognosis in early breast cancer. The presence of HER2-positive CTCs has been also associated with significantly decreased disease-free and overall survival. We hereby assessed the HER2 status of CTCs in HER2-negative patients with early breast cancer, before the initiation of adjuvant chemotherapy and during follow-up. Methods: Double staining immunofluorescent experiments using pancytokeratin (A45-B/B3) and HER2 antibodies were performed in peripheral blood mononuclear cells (PBMCs) of patients. Patients were evaluated before adjuvant therapy (n=103) and during follow-up (n=290) at intervals ranging from 6 months to 20 years post-chemotherapy. Results: CTCs were detected in 28 (27.2%) out of 103 patients pre-chemotherapy and in 94 (32.4%) out of 290 during follow-up. The mean CTC count detected at ≤2 years of follow-up was not significantly different compared to baseline [3.4 CTCs (range 1-13) vs 2.9 (range 1-12), respectively]. However, this value showed a significant decrease from 2-5 to ≥10 years of follow-up (4.2, range 1-11 vs. 1.8, range 1-4). Among CTC-positive patients, CTCs expressing HER2 were detected in 21 (75%) and in 73 (77.7%) patients pre-chemotherapy and during follow-up, respectively. The mean proportion of HER2-positive CTCs per patient was 73.5% pre-chemotherapy and 67% at follow-up. This proportion showed a significant increase at follow-up time points ≤2, 2-5 and 5-10 years [52% (p=0.0027), 65.6% (p=0.0476) and 69% (p=0.0440), respectively] compared to ≥10 years (89.2%). Conclusions: These data demonstrate that CTCs persist during follow-up in a significant percentage of early breast cancer patients. Similarly, HER2 positive CTCs are detected in a significant proportion of patients both at baseline and during follow-up. Mean CTC count appears to decrease after 10 years, whereas the population of HER2 positive CTCs seems to increase during follow-up. These results suggest that targeting HER2-positive CTCs may have implications for the prevention of late relapses.

Citation Format: Markomanolaki H, Mavroudis D, Kallergi G, Vetsika E-K, Stratigos M, Makrigiannaki K, Georgoulias V, Agelaki S. HER2 expression on circulating tumor cells before adjuvant chemotherapy and during follow-up in patients with HER2-negative early breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-02-03.
Abstract IA13: Inhibiting the Wnt pathway with selective anti-Frizzled synthetic antibodies
Authors: Steinhart Zachary , Hart Traver , Sidhu Sachdev , Moffat Jason , Angers Stephane
Published: May 2016

Secreted Wnt glycoproteins regulate intracellular signaling pathways important for embryonic development and adult tissue homeostasis. Misregulation of Wnt signalling is frequent in human cancers. Wnt ligands are recognized at the surface of cells by various receptor complexes that are differentially expressed and determine context-dependent cellular responses. In humans, 16 Wnt ligands interact directly with 10 Frizzled seven transmembrane proteins through their extracellular cysteine rich domain (CRD). Wnts also interact with various co-receptors, such as LRP5/6, ROR1/2, RYK, PTK7, which engage different downstream signaling pathways. While genetic analysis of mouse knockouts has revealed specific roles for different Wnt receptors and co-receptors during embryonic development, relatively little is known about their respective functions during adult tissue homeostasis or in the initiation and progression of human diseases such as cancer. There is a paucity of reagents allowing the selective and temporal pharmacological inhibition of Wnt receptors. We are employing phage-display technology to identify high affinity synthetic blocking monoclonal antibodies (mAbs) against all human Wnt receptors. To date we have isolated a collection of anti-receptor antibodies exhibiting unique selectivity and functionality profiles. Our lead anti-Frizzled mAbs targeting a subset of Frizzled proteins inhibit Wnt-promoted activation of the TopFlash reporter with low nanomolar potency. These mAbs also exhibit dose dependent anti-proliferative efficacies against various pancreatic cancer cell lines grown in vitro and as xenografts in mice.

These reagents will be useful to probe the function of specific Wnt receptors in tissue homeostasis and human diseases and will lead to novel therapeutic agents for their treatment.

Our lab is also employing whole genome CRISPR screening approach to identify genotype specific vulnerabilities in cancer cells. These efforts have identified specific Frizzled important for cancer cells proliferation and is guiding our antibody development program.

Citation Format: Zachary Steinhart, Traver Hart, Sachdev Sidhu, Jason Moffat, Stephane Angers. Inhibiting the Wnt pathway with selective anti-Frizzled synthetic antibodies. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA13.
Abstract A09: The role of asparagine in glutamine-independent proliferation of breast cancer cells
Authors: Pavlova Natalya N. , Thompson Craig B.
Published: May 2016

The majority of proliferating cells utilize the carbon backbone of glutamine as a major anaplerotic input into the TCA cycle. In addition, glutamine serves as a donor of reduced nitrogen for the biosynthesis of purine and pyrimidine nucleotides, as well as for a number of non-essential amino acids. Thus, cells rely on external sources of glutamine for biomass accumulation and growth. However, recent data indicate that some cancer cell types – luminal breast cancer lines in particular – are able to proliferate in the absence of exogenous glutamine. Furthermore, luminal breast cancer lines display increased expression of GLUL (glutamine synthetase) and reduced expression of GLS1 (glutaminase), when compared to basal subtype.

We sought to identify key metabolic determinants of glutamine-independent proliferation. As our preliminary data indicate, the presence of amino acid asparagine is required for the proliferation of luminal breast cancer cells as well as normal breast epithelial cells in the setting of glutamine deprivation. Both asparagine and glutamine contain amide groups in their respective side chains and are thus structurally similar to each other. However, most normal mammalian tissues – with the exception of the liver and the kidney – are unable to catabolize asparagine, making it essentially metabolically inert for the majority of cell types. Our group has previously shown that asparagine suppresses cell death in cells that depend on glutamine for survival. In this study, we attempt to elucidate the mechanism by which asparagine facilitates the biomass accumulation and proliferation of glutamine-independent cell types. First, we investigate whether luminal breast cancer cells may possess an ability to catabolize asparagine in a manner similar to glutaminolysis and thus use it as an alternative source of reduced nitrogen and carbon in a setting of glutamine deprivation. Second, we explore a potential regulatory metabolic function of asparagine, whereby it may regulate cellular glutamine synthesis and thus enable proliferation in conditions of glutamine deprivation.

Citation Format: Natalya N. Pavlova, Craig B. Thompson. The role of asparagine in glutamine-independent proliferation of breast cancer cells. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A09.
Abstract A20: Mitochondrial phosphoenolpyruvate carboxykinase (PCK2) regulates metabolic adaptation and enables glucose-independent tumor cell growth
Authors: Vincent Emma E. , Sergushichev Alexey , Griss Takla , Artyomov Maxime N. , Jones Russell G.
Published: May 2016

Cancer cells must adapt metabolically to survive and proliferate when nutrients are limiting. Here we used combined transcriptional-metabolomic network analysis to identify metabolic pathways that support glucose-independent tumor cell growth. We found that glucose deprivation stimulated the re-wiring of the tricarboxylic acid (TCA) cycle and early steps of gluconeogenesis to promote cell proliferation under low glucose. Glucose limitation promoted the production of phosphoenolpyruvate (PEP) from glutamine, which was used to fuel biosynthetic pathways normally sustained by glucose, including serine and purine biosynthesis. Mitochondrial PEP-carboxykinase (PCK2) was required for this glutamine-dependent metabolic reprogramming. PCK2 expression was dependent on the hypoxia-inducible factors (HIFs), and required to maintain tumor cell proliferation under limiting glucose availability. Elevated PCK2 expression is observed in several human tumor types, and enriched in tumor tissue from non-small cell lung cancer (NSCLC) patients. Our results define a novel role for PCK2 in cancer cell metabolic reprogramming that promotes glucose-independent cell growth and metabolic stress resistance in human tumors.

Citation Format: Emma E. Vincent, Alexey Sergushichev, Takla Griss, Maxime N. Artyomov, Russell G. Jones. Mitochondrial phosphoenolpyruvate carboxykinase (PCK2) regulates metabolic adaptation and enables glucose-independent tumor cell growth. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A20.
Abstract B27: Kras alters expression of asparagine synthetase (Asns) in non-small cell lung cancer (NSCLC) and protects tumors during nutrient stress
Authors: Gwinn Dana M. , Sweet-Cordero Alejandro
Published: May 2016

Kras is a small GTPase that functions in the transmission of extracellular mitogenic stimuli, and is one of the most frequently mutated genes in non-small cell lung cancer (NSCLC). Previously, Kras has been demonstrated to play a role in tumor metabolism in certain cell types and cancers, but this has yet to be analyzed in the context of NSCLC. We have analyzed how Kras changes metabolic gene expression by expressing a doxycycline-inducible hairpin against Kras in 4 NSCLC cell lines. One of the most regulated metabolism genes is asparagine synthetase (Asns), which transfers the γ-amino group of glutamine to aspartate, yielding glutamate and asparagine. We find elevated levels of Asns in Kras mutant tumors, and that expression of Asns correlates with poor patient outcome. Knockdown of Asns in the absence of exogenous asparagine in the media results in inhibition of cell growth and induction of apoptosis that is rescued by addition of asparagine. Additionally, under conditions of low glutamine levels, knockdown of Asns sensitizes cells to apoptosis, and overexpression of Asns is protective under these conditions. We also find a role for the glutaminase-activity of Asns in glutamine-mediated anapleurosis of the TCA cycle. These observations suggest Asns may be an interesting therapeutic target for NSCLC tumors with mutations in Kras.

Citation Format: Dana M. Gwinn, Alejandro Sweet-Cordero. Kras alters expression of asparagine synthetase (Asns) in non-small cell lung cancer (NSCLC) and protects tumors during nutrient stress. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B27.
Abstract B32: FOXOs support the metabolic requirements of normal and tumor cells by regulating IDH1 expression
Authors: Charitou Paraskevi , Rodriguez-Colman Maria , Gerrits Johan , Verhoeven-Duif Nanda , Burgering Boudewijn
Published: May 2016

FOXO transcription factors are considered bona fide tumor suppressors, however recent studies showed FOXOs are also required for tumor survival. Here we identify FOXOs as transcriptional regulators of IDH1. FOXOs regulate IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. In cancer cells carrying mutant IDH1, FOXOs likewise regulate mutant IDH1 expression and maintain the levels of the oncometabolite 2-hydroxyglutarate, which stimulates cancer cell proliferation likely by repressing differentiation. Combined, our data provide a new paradigm for the paradoxical role of FOXOs in both tumor suppression and promotion. Furthermore these data suggest a role for FOXOs in maintaining the de-differentiated state by regulating α-ketoglutarate and/or 2-hydroxyglutarate levels. Indeed, in models of differentiation (e.g. 3T3-L1 differentiation towards adipocytes) loss of FOXO, as well as loss of IDH1 expression repress differentiation and we are currently further exploring the molecular underpinnings.

Note: This abstract was not presented at the conference.

Citation Format: Paraskevi Charitou, Maria Rodriguez-Colman, Johan Gerrits, Nanda Verhoeven-Duif, Boudewijn Burgering. FOXOs support the metabolic requirements of normal and tumor cells by regulating IDH1 expression. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B32.
Abstract B44: Functional identification of a mitochondrial glutamine carrier using isotope tracers
Authors: Metallo Christian
Published: May 2016

This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR07) of the Conference Proceedings.

Citation Format: Christian Metallo. Functional identification of a mitochondrial glutamine carrier using isotope tracers. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B44.
Abstract B59: Autophagy mediates senescence and supports survival upon treatment with anti-mitotic drugs
Authors: Bing Cheng , Ke Guo , Wong Alex , Crasta Karen
Published: May 2016

Anti-mitotic drugs such as paclitaxel and vinblastine have been used as front-line therapies for the treatment of many cancers. These agents induce activation of a spindle assembly checkpoint (SAC), which leads to a prolonged mitotic arrest that culminates in cell death. However, this anti-proliferative mechanism is often impeded by the development of chemo-resistance. A major cause of resistance is mitotic slippage. Mitotic slippage is a process whereby cells exit mitosis and undergo an abnormal cytokinesis failure despite an active SAC. Till now the mechanisms leading to mitotic slippage and post slippage survival are not fully understood. Here we find that cancer cells “slip”, form multinucleated cells and undergo senescence upon treatment with anti-mitotic drugs. Our data indicate that autophagy plays an important role in senescence induction. Inhibition of autophagy via pharmacological drugs or silencing of autophagy-associated genes could over-ride senescence. This promotes DNA damage accumulation, which attenuates long term survival upon anti-mitotic drug treatment. Taken together, our data suggest that autophagy mediated-senescence contributes to chemo-resistance and could serve as a potential combinatorial target with anti-mitotic drugs in future clinical trials.

Note: Guo Ke has been added to the author list. The online version of this abstract differs from the original print proceedings.

Citation Format: Cheng Bing, Guo Ke, Alex Wong, Karen Crasta. Autophagy mediates senescence and supports survival upon treatment with anti-mitotic drugs. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B59.
Abstract B73: Increased serum fatty acyl carnitine levels may indicate development of advanced colorectal adenoma
Authors: Perera Thushanthi H. , Murphy Gwen , Young Matthew R. , Colburn Nancy H. , Lanza Elaine , Cross Amanda J. , Bobe Gerd
Published: May 2016

Introduction: Colorectal cancer is the third most common cancer worldwide. Early detection of colorectal cancer dramatically improves survival rates. Thus, identification of early indicators may greatly reduce morbidity and mortality associated with this malignant cancer. The aim of this study was to identify early indicators of advanced colorectal adenoma in prospectively collected serum.

Methods: We used a nested case-control study design in the Polyp Prevention Trial (PPT). All participants had a recent history of colorectal adenoma at baseline and underwent a colonoscopy at baseline and 4 years thereafter. 103 participants with an advanced adenoma 4 years after baseline were matched with 103 participants who remained polyp and adenoma free. Serum metabolites were measured by liquid chromatography/mass spectroscopy +/- electrospray ionization and gas chromatography/mass spectroscopy in samples collected at baseline (T0) and at the end of year 3 (T3). Changes in serum metabolite levels were compared overall and stratified by metabolic pathways using paired t-tests (parametric and non-parametric).

Results: A total of 454 known serum metabolites were measured; of these, 294 were above the limit of detection in ≥90% of samples. A total of 100 metabolites changed significantly in adenoma cases at p < 0.05 (13 down- and 87 up-regulated) and 51 metabolites changed in adenoma cases at q < 0.05 (7 down- and 44 up-regulated) The most affected metabolic pathways were: fibrinogen cleavage proteins (all 3 up-regulated at q < 0.05), fatty acyl carnitines (7 of 9 up-regulated at p < 0.05 and 4 of 9 up-regulated at q < 0.05), nucleotide sugars (6 of 9 up-regulated at p < 0.05 and 3 of 9 up-regulated at q < 0.05), and non-esterified long-chain unsaturated fatty acids (9 of 12 up-regulated at p < 0.05 and 4 of 12 up-regulated at q < 0.05). 24 metabolites differed in ΔT3-T0 between advanced adenoma cases and controls at p < 0.05. The metabolic pathway most affected was fatty acyl carnitines (9 of 9 up-regulated compared to controls at p < 0.10 and 5 of 9 up-regulated compared to controls at p < 0.05).

Conclusions: Increased serum fatty acyl carnitine levels may serve as early indicators of the development of advanced colorectal adenoma.

Citation Format: Thushanthi H. Perera, Gwen Murphy, Matthew R. Young, Nancy H. Colburn, Elaine Lanza, Amanda J. Cross, Gerd Bobe. Increased serum fatty acyl carnitine levels may indicate development of advanced colorectal adenoma. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B73.
Abstract B78: The influence of breast cancer on the metabolic status of myeloid cells
Authors: Huang Li-Rung , Jian Shiou-Ling , Jhou Yi-Jyun
Published: May 2016

Breast cancer is the most common cancer and the second leading cause of cancer death in women. Except for surgery, radiotherapy, chemotherapy and targeting therapy, breast cancer vaccine is now actively developed. However, the outcome of most therapeutic cancer vaccines was not satisfying probably due to the induction of immunosuppression in cancer patients. Myeloid-derived suppressor cells (MDSCs) are one of the major immunoregulatory cell populations, which play important roles not only in T-cell suppression but also in angiogenesis, lymphangiogenesis and metastasis during tumor progression. MDSCs are heterogeneous populations of immature myeloid cells, which expand and developed in responses to growth factors, cytokines and chemokines derived from cancer cells and then are released from bone marrow to peripheral tissues including tumor site. It is well known as tumor cells could influence the activation and proliferation of myeloid cells through release of cytokines during tumor progression to result in the accumulation of large number of MDSCs in cancer patients. However little is known about the relevance of metabolic status and accumulation of MDSCs in cancer patients during tumor progression. We therefore try to elucidate the metabolic changes during differentiation of myeloid cells into MDSCs.

To intensively study the transcriptional program of MDSCs in comparison to their healthy counterparts, we perform DNA microarray analysis using mRNAs from monocytic MDSCs, granulocytic MDSCs from primary tumor sites of 4T1 tumor-bearing mice, monocytes and neutrophils from bone marrow of healthy mice. MDSCs up-regulated mRNA levels of genes related to angiogenesis and lymphangiogenesis e.g. VEGFa, angiopoietin 1, PROK2 (BV8), MMP9, MMP12, MMP13 and MMP14, genes of pro-inflammatory cytokines e.g. IL-1α, IL-6 and TNFα, genes of immunosuppressive molecules e.g. arginase 1, iNOS, PD-L1, PD-L2, CD83 and CD155. We are currently examining the metabolomics of these MDSCs and their healthy counterparts and expect to prove the association of certain metabolic changes with the differentiation of MDSCs.

Citation Format: Li-Rung Huang, Shiou-Ling Jian, Yi-Jyun Jhou. The influence of breast cancer on the metabolic status of myeloid cells. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B78.
Abstract IA11: Systematic approaches to understanding cellular metabolism
Authors: Sabatini David M.
Published: May 2016

mTOR is the target of the immunosuppressive drug rapamycin and the central component of a nutrient- and hormone-sensitive signaling pathway that regulates cell growth and proliferation. We now appreciate that this pathway becomes deregulated in many human cancers and has an important role in the control of metabolism and aging. We have identified two distinct mTOR-containing proteins complexes, one of which regulates growth through S6K and another that regulates cell survival through Akt. These complexes, mTORC1 and mTORC2, define both rapamycin-sensitive and insensitive branches of the mTOR pathway. I will discuss new results from our lab on the regulation and functions of the mTORC1 and mTORC2 pathways.

Citation Format: David M. Sabatini. Systematic approaches to understanding cellular metabolism. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr IA11.
Abstract IA25: Obesity, metabolism, and cancer: Mechanistic insights from transdisciplinary studies
Authors: Hursting Stephen David
Published: May 2016

The prevalence of obesity, an established risk and progression factor for many cancers, has risen steadily for the past several decades in the US and many other countries. Unfortunately, the mechanisms underlying the obesity and cancer connection are poorly understood, and new targets and strategies for offsetting the impact of obesity on cancer risk are urgently needed. We have established in a series of dietary, genetic and pharmacologic studies using genetically-engineered mouse models (GEMMs) of mammary and pancreatic cancer, that insulin and insulin-like growth factor-1 receptor signaling via the Akt/mTOR pathway, as well as NF-kB-mediated inflammatory signals, are central to many of the pro-cancer effects of obesity as well as the anti-cancer effects of calorie restriction (CR). We have also linked our mouse model studies with clinical trials and epidemiologic studies to accelerate the translation of our preclinical findings in humans. Our recent work has focused on testing the hypothesis that moderate weight loss alone does not reverse the cancer-associated metabolic and inflammatory perturbations that occur with chronic obesity. We have found in our GEMMs and human studies that chronic obesity results in epigenetic reprogramming, including global changes in DNA and histone methylation and microRNA biogenesis, and have established that normalization of weight is insufficient to reverse the obesity-induced epigenetic and metabolic changes and normalize cancer susceptibility. Our transdisciplinary studies suggest that combining weight loss regimens with interventions that target the obesity-associated epigenetic, metabolic and/or inflammatory changes may be an effective strategy for breaking the obesity-cancer link.

Citation Format: Stephen David Hursting. Obesity, metabolism, and cancer: Mechanistic insights from transdisciplinary studies. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr IA25.
Abstract A031: CD8+T cells fail to form an effector memory in glioblastoma patients treated with dendritic cell immunotherapy in combination with chemotherapy
Authors: Pellegatta Serena , Eoli Marica , Anghileri Elena , Pessina Sara , Antozzi Carlo , Frigerio Simona , Cantini Gabriele , Bruzzone Maria Grazia , Pollo Bianca , Parati Eugenio A. , Finocchiaro Gaetano
Published: May 2016

A critical requirement of an efficient cancer immunotherapy is the generation of long-lasting, specific memory.

In a clinical trial active at Istituto Besta, first diagnosis glioblastoma (GBM) patients, with post-surgery volume ≤10 cc, underwent leukapheresis before radiotherapy and chemotherapy with the alkylating agent temozolomide (TMZ). Three intradermal injections of mature dendritic cells (DCs) loaded by autologous tumor lysates were done before adjuvant chemotherapy. Subsequent 4 injections were performed in association with six cycles of adjuvant TMZ. Peripheral blood lymphocytes (PBLs) were analyzed by flow cytometry to characterize immune response before and after DC vaccines.

The ratio of vaccination/baseline frequencies and counts (V/B ratio) of all of the immunological parameters for each patient was calculated, and the median of all of the observations used as the cut off value to separate patients. V/B ratio was correlated with the progression free survival (PFS) of each patient. Preliminary results from the interim analysis on 24 patients showed that an increased NK, but not CD8+ T cell response was significantly associated with prolonged survival (p<0.005).

In a group of responder patients (PFS>12), during the first three vaccines, CD8+ T cells underwent a rapid expansion and produced higher levels of IFN-γ compared to the baseline (p<0.02).

After the third vaccine and TMZ administration, primed CD8+ T cells failed to form an effector memory phenotype (CCR7negCD45RAnegCD62Llow/neg).

Our results support a possible interference of adjuvant chemotherapy on effector memory formation. Further investigations are required to understand how memory T cells behave in response to repeated exposure to TMZ.

Citation Format: Serena Pellegatta, Marica Eoli, Elena Anghileri, Sara Pessina, Carlo Antozzi, Simona Frigerio, Gabriele Cantini, Maria Grazia Bruzzone, Bianca Pollo, Eugenio A. Parati, Gaetano Finocchiaro. CD8+T cells fail to form an effector memory in glioblastoma patients treated with dendritic cell immunotherapy in combination with chemotherapy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A031.
Abstract B032: Targeting the PD-1/PD-L1 immune evasion axis with DNA aptamers
Authors: Prodeus Aaron , Gariepy Jean
Published: May 2016

Blocking the immunoinhibitory PD-1:PD-L1 pathway using monoclonal antibodies has led to dramatic clinical responses by reversing tumor immune evasion and provoking robust and durable anti-tumor responses. Anti-PD-1 antibodies have now been approved for the treatment of melanoma, and are being clinically tested in a number of other tumor types as both a monotherapy and as part of combination regimens. Here, we report the development of DNA aptamers as synthetic, non-immunogenic antibody mimics, which bind specifically to the murine extracellular domain of PD-1 and block the PD-1:PD-L1 interaction. These aptamers did not bind to closely related proteins including human PD-1. One such aptamer, MP7, functionally inhibits the PD-L1-mediated suppression of IL-2 secretion in primary murine T-cells. A PEGylated form of MP7 retains the ability to block the PD-1:PD-L1 interaction, and significantly suppresses the growth of PD-L1+ colon carcinoma cells in-vivo with a potency equivalent to an antagonistic anti-PD-1 antibody. Importantly, the anti-PD-1 DNA aptamer treatment was not associated with off-target TLR-9-related immune responses. Due to the inherent advantages of aptamers including their lack of immunogenicity, low cost, long shelf life, and ease of synthesis, such PD-1 antagonistic aptamers may represent an attractive alternative over antibody-based anti PD-1 therapeutics.

Citation Format: Aaron Prodeus, Jean Gariepy. Targeting the PD-1/PD-L1 immune evasion axis with DNA aptamers. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B032.
Long-Term Outcomes of the Implant of a Periurethral Constrictor for Stress Urinary Incontinence Following Radical Prostatectomy
Authors: Favro Michele , Billia Michele , Volpe Alessandro , Zacchero Monica , Terrone Carlo
Published: May 2016

Objectives: To assess morbidity, effectiveness and quality of life (QoL) of implant of Silimed periurethral constrictor (PC) in a consecutive series of patients who had stress urinary incontinence following radical prostatectomy. Material and Methods: A prospective non-randomized study designed on patients who underwent implant of Silimed PC. Primary end point was postoperative morbidity and secondary end points were effectiveness of implant and QoL. We performed a sub-analysis of men who received previous radiation and we compared the subpopulation with radiation-naïve patients. Results: Nineteen patients (31.6%) received pelvic radiation therapy prior implant. All procedures were completed successfully with median operative time of 55 (IQR 50-62.5) min. We recorded 47 (78.3%) postoperative complications in 30 men. Twenty-three men (38.3%) developed urethral erosion at median follow-up of 27.5 (IQR 21-35) months, and 1 man (1.9%) had rectourethral fistula at 2 months. Risk of urethral erosion increased significantly among patients who received radiation (63.1 vs. 26.8%; p < 0.001). In 12 cases (20%), we recorded malfunctioning of the reservoir requiring replacement. Conclusion: The implant of Silimed device is not safe due to a high risk of urethral erosion. Careful patient selection and detailed counseling are mandatory when considering the implant of PC in adult patients.
Different Pathophysiology of Gastritis between East and West? An Asian Perspective
Authors: Suzuki Hidekazu , Mori Hideki
Published: May 2016

Background: The incidence of gastric cancer in Asia is higher than that in Europe and Northern America. Helicobacter pylori infection is the most important factor for the development of atrophic gastritis and gastric cancer. The geographical distribution of the prevalence and virulence factors of H. pylori are important to understand the difference between gastritis in the East and West. Summary: Articles comparing gastritis cases between eastern and western countries showed that the severity of gastritis is closely related to the risk of gastric cancer, and the severity of gastritis is more advanced in East Asia. Although the prevalence of H. pylori infection is closely associated with the incidence of gastric cancer in European countries, the severity of gastritis and the high incidence of gastric cancer in East Asia are not dependent only on the prevalence of H. pylori infection itself. From the viewpoint of the virulence factors of H. pylori, the East Asian CagA-positive strain (EPIYA motif ABD type) is peculiar in East Asia. Considering comprehensively the geographical distribution of H. pylori subtypes is the most important factor among all prospected risk factors for the incidence of gastric cancer and the rate of development of gastritis. While eating habits, such as salty foods, vegetables and fruits, might influence the progression of gastritis, such factors might be responsible for the geographic heterogeneity of gastritis. Key Message: East Asian CagA-positive H. pylori is the strongest risk factor for gastric carcinogenesis and the development of gastritis.
The Association between Central Adiposity and Autonomic Dysfunction in Obesity
Authors: Fidan-Yaylali Güzin , Yaylali Yalin Tolga , Erdogan Çağdaş , Can Beray , Senol Hande , Gedik-Topçu Bengi , Topsakal Senay
Published: May 2016

Objective: To determine the relationship between central adiposity parameters and autonomic nervous system (ANS) dysfunction. Subjects and Methods: The study included 114 obese individuals without any cardiovascular risk factors. Weight (in kg), height (in m), and waist circumference (WC; in cm) were measured and body mass index was calculated. Echocardiographic examination was performed to measure left ventricular mass and epicardial fat thickness (EFT). All the participants underwent an exercise test and electrophysiological evaluation using electromyography. Heart rate recovery (HRR) at 1-5 min, R-R interval variation at rest and during hyperventilation, and sympathetic skin response were measured. Pearson's correlation analysis was used. Multiple linear regression analysis was used to identify the factors associated with autonomic dysfunction. Results: The HRR at 1-5 min was negatively correlated with WC and age (WC-HRR1: r = -0.32; WC-HRR2: r = -0.31; WC-HRR3: r = -0.26; WC-HRR4: r = -0.23; WC-HRR5: r = -0.21; age-HRR2: r = -0.32; age-HRR3: r = -0.28; age-HRR4: r = -0.41; age-HRR5: r = -0.42). Age was the only independent predictor of reduced HRR at 1-5 min. In addition, WC predicted a reduced HRR at 3 min. There were no significant associations between central obesity and electrophysiological parameters. EFT was not associated with ANS dysfunction. Conclusion: In this study, central adiposity and aging were associated with ANS dysfunction in obese individuals. The WC could be a marker of ANS dysfunction in obese individuals without any cardiovascular risk factors. The HRR assessment at a later decay phase could be more valuable for evaluating ANS function than during early recovery.
Determinação sérica de colesterol e triglicérides em cavalos soroprodutores alimentados com concentrados com teores de 15% ou 22% de proteína bruta
Authors: Betiol Patrícia Stocco , Távora Juarez Pinto Fernandes , Parra Andrea Cristina , Sucupira Maria Cláudia Araripe , Gregory Lilian
Published: May 2016

A produção de soro-hiperimune em eqüinos ainda é fundamental para obtenção do soro utilizado no tratamento de algumas enfermidades como o tétano e a difteria. Para verificar o possível benefício da utilização de concentrados hiperprotéicos na dieta dos cavalos soroprodutores da Fazenda São Joaquim do Instituto Butantan-SP, foram analisados os teores séricos de colesterol e triglicérides de 32 animais, pertencentes ao plantel de produção de soro antidiftérico. Estes foram distribuídos, ao acaso, em dois grupos de 16 eqüinos. Os animais do grupo A receberam concentrado com 15% de proteína bruta (PB) e os animais do grupo B receberam concentrado com 22% de PB. As amostras de soro foram obtidas em dois ciclos de produção nos momentos anteriores à inoculação do antígeno, antes das sangrias de produção e nos dias 15, 30 e 45 de descanso. As concentrações de triglicérides foram maiores no grupo B no dia 58 do primeiro ciclo (p<0,001) e, no segundo ciclo, foram maiores no grupo A nos dias 95 e 137 (p<0,04) e no grupo B no dia 109 (p<0,04). Não houve diferença entre os grupos para as concentrações séricas de colesterol. Este trabalho concluiu que embora as concentrações séricas de triglicérides e colesterol sejam sensíveis ao processo de produção de plasma-hiperimune antidifitérico, os resultados encontrados não foram suficientes para afirmar se há benefício ou não na utilização de concentrado hiperprotéico (22% PB) em cavalos produtores de soro-hiperimune anti-difteria em dois ciclos de produção
Efeito da suplementação de linhaça, óleo de canola e vitamina e na dieta sobre a oxidação dos ácidos graxos na gema dos ovos de galinhas poedeiras
Authors: Pita Maria Carolina Gonçalves , Piber Neto Eduardo , Mendonça Junior Cássio Xavier
Published: May 2016

A presente pesquisa teve como objetivo estudar o efeito de fontes de ácidos graxos poliinsaturados- óleo de canola e/ou semente de linhaça- com diferentes concentrações de vitamina E suplementar sobre o teor de produtos de oxidação de ácidos graxos na gema de ovos de galinhas. Utilizou-se 288 galinhas da linhagem Babcock que receberam dietas com 6% de óleo de canola, 20% de semente de linhaça moída ou 3% de óleo de canola e 10% de semente de linhaça moída com teores de 0, 100 e 200 UI/kg de a-tocoferol, para análise estatística dos resultados empregou-se arranjo fatorial 3X3 em blocos casualizados. Os grupos que receberam óleo de canola tiveram menores concentrações de malonaldeído (menor oxidação) na gema dos ovos que aqueles alimentados com linhaça, em ovos crus sem armazenamento e nos cozidos após armazenamento. Os ovos crus tiveram as menores concentrações de produtos de oxidação dos ácidos graxos. Os grupos de ovos cozidos, que receberam 100 e 200UI/kg de vitamina E na dieta, tiveram menores teores de malonaldeído na gema dos ovos que os grupos não suplementados
Hidrolisado de penas como fonte de proteína para ratos
Authors: Grazziotin Adriane , Pimentel Fernanda Araújo , Jong Erna Vogt De , Brandelli Adriano
Published: May 2016

A proteína da pena é uma boa fonte proteica para dietas de animais, sendo um material de grande disponibilidade como subproduto da produção avícola. Neste trabalho, um hidrolisado protéico de penas produzido pelo microrganismo queratinolítico Vibrio sp. kr2 foi avaliado como suplemento em rações. Ratos da linhagem Wistar foram alimentados com sete dietas experimentais (n = 6 ratos por dieta) contendo diferentes fontes de proteína: caseina (CAS), proteína de soja, hidrolisado de pena, farinha de pena, e proteína de soja suplementada com 10 ou 20% (w/w) hidrolisado de pena, ou 20% hidrolisado de pena suplementado com metionina. Os valores de ganho de peso, consumo, digestibilidade verdadeira, coeficiente de eficiência alimentar, coeficiente de eficiência proteica (PER) e eficiência líquida proteica (NPR) foram similares para as dietas contendo proteína de soja e proteína de soja suplementada com 20% hidrolisado de pena e metionina. Valores inferiores para todos parâmetros nutricionais foram observados para as dietas contendo 10 ou 20% hidrolisado de pena, hidrolisado de pena e fariha de pena. A fonte protéica influenciou no peso final do fígado, rins e coração, porém as diferenças não foram significativas para cérebros. Estes resultados indicam que o hidrolisado de penas pode ser usado como fonte de proteína suplementar na formulação de rações desde que suplementados com metionina
Glândula mamária do mocó (Kerodon rupestris - Wied Neuwied, 1820): aspectos morfológicos
Authors: Lima Marcelo Cardoso de , Bonatelli Marina , Oliveira Moacir Franco de , Miglino Maria Angélica , Goiozo Paulo Felipe Izique , Martins Simone Maria Massami Kitamura , Carvalho Ana Flávia de
Published: May 2016

Procurando colaborar com a exploração zootécnica racional dos mocós (Kerodon rupestris) foi descrita a morfologia da glândula mamária destes roedores, que por sua vez podem tornar-se uma fonte de alimento para população nordestina. Foram utilizados cinco animais cedidos pelo Centro de Multiplicação de Animais Silvestres (CEMAS) da pela Escola Superior de Agricultura de Mossoró (ESAM) registrado junto ao IBAMA como criadouro científico sob o número 12.492-0004. As glândulas mamárias foram retiradas através de dissecação e foram fotografadas. Cada animal apresentou duas glândulas mamárias localizadas na região inguinal. Histologicamente a glândula mamária era composta por uma grande quantidade de lóbulos, repletos de glândulas túbulos-alveolares com epitélio simples cúbico. Na papila mamária fibras musculares apresentaram-se dispostas de modo circular, o que possivelmente auxilia na contração para excreção do leite.
Dimensões, massa e volume do baço em tartarugas (Trachemys scrypta elegans, Wied,1839)
Authors: Faria Marcelo Domingues de , Seyfert Carlos Eduardo
Published: May 2016

O objetivo deste estudo foi verificar as dimensões, massa e volume do baço em tartarugas (Trachemys scripta elegans WIED, 1839) estabelecendo correlação com as dimensões, massa e volume corporais. Para a confecção deste trabalho, utilizou-se vinte animais, provenientes do Instituto de Psicologia da Universidade de São Paulo, coletados após a eutanásia que, levados ao Laboratório de Anatomia da Faculdade de Medicina Veterinária e Zootecnia da mesma universidade, tiveram suas dimensões, massa e volume corporais aferidos. Então, retirou-se o plastrão, expondo sua cavidade celomática, removendo o baço para realizar as mensurações. Apesar dos animais terem sido criados num mesmo ambiente, sob as mesmas condições ambientais e abatidos no mesmo período do ano, concluiu-se que não há correlação entre as dimensões do baço e as dimensões corporais, onde, animais menores podem apresentar o baço com maiores proporções do que tartarugas maiores, variando conforme as condições individuais - fato que ocorre com as demais espécies animais.
Influência da temperatura e do fluxo de ar sobre o consumo de ração e ganho de peso em ratos Wistar (Rattus norvegicus) mantidos em sistema microambiental
Authors: Martinewski Alexandre , Souza Nívea Lopes de , Merusse José Luiz Bernardino
Published: May 2016

Ratos wistar foram mantidos individualmente, em gaiolas metabólicas de arame, sem abrigo, em sistema microambiental, sob fluxo direto de ar a 0,6 m/s, nas temperaturas de 22º, 24º, 26º, 28º e 30º C. O consumo de ração e o ganho de peso foram comparados do final de 5 dias (ANOVA; Tukey-Kramer). No total, sete grupos de 10 animais cada foram comparados. Para a faixa de 22ºC foram utilizados três grupos, sendo um grupo experimental e dois grupos controles. Um deles foi mantido em condições ambientais semelhantes a biotérios convencionais sob ventilação geral diluidora (VGD) - C1. O outro grupo controle (C2) foi mantido no interior do equipamento de ventilação microambiental, porém, sem o direcionamento de ar, simulando a VGD. Os resultados obtidos demonstram claramente que animais mantidos sob ventilação microambiental direta a 26º, 28º e 30ºC apresentam o mesmo ganho de massa corpórea que animais do grupo C1. Os grupos de animais mantidos a 22º e 24ºC, apresentaram menor ganho de massa corpórea quando comparados a C1 (p<0,001 e p<0,01 respectivamente). O ganho de peso de todos os grupos experimentais, quando comparado ao C2, apresenta diferenças estatísticas, exceto o mantido a 30ºC que apresentou índice de ganho de peso equivalente a C2. O consumo de ração de todos os grupos se manteve constante. Somente o grupo E5 apresentou uma redução no consumo de ração quando comparado aos grupos C1 e C2 (p<0,05 para as duas comparações).
Sarcocystosis in Mithuns Bos frontalis - a report
Authors: Abraham S.S. , Jayakumar C.S. , Alexander J.
Published: May 2016

A case of Sarcocystosis in Mithuns at the Zoological Park, Thiruvananthapuram is reported. Histological changes in the heart muscle is described
Oncological miR-182-3p, a Novel Smooth Muscle Cell Phenotype Modulator, Evidences From Model Rats and Patients
Authors: Sun Lan , Bai Yongyi , Zhao Rui , Sun Tao , Cao Ruihua , Wang Fuyu , He Guorong , Zhang Wen , Chen Ying , Ye Ping , Du Guanhua
Published: May 2016

Objective—

Vascular smooth muscle cell (VSMC) phenotype change is a hallmark of vascular remodeling, which contributes to atherosclerotic diseases and can be regulated via microRNA-dependent mechanisms. We recently identified that asymmetrical dimethylarginine positively correlates to vascular remodeling–based diseases. We hypothesized that asymmetrical dimethylarginine induces smooth muscle cell (SMC) phenotypic change via a microRNA-dependent mechanism.

Approach and Results—

Microarray analysis enabled the identification of downregulation of miR-182-3p in asymmetrical dimethylarginine–treated human aortic artery SMCs. The myeloid-associated differentiation marker (MYADM) was identified as the downstream target of miR-182-3p and implicated to contribute to miR-182-3p knockdown–mediated SMC phenotype change, which was evidenced by the increased proliferation and migration and reduced expression levels of phenotype-related genes in human aortic artery SMCs through the ERK/MAP (extracellular signal-regulated kinase/mitogen-activated protein) kinase–dependent mechanism. When inhibiting MYADM in the presence of miR-182-3p inhibitor or overexpressing MYADM in the presence of pre-miR-182-3p, human aortic artery SMCs were reversed to the differentiation phenotype. In vivo, adeno-miR-182-3p markedly suppressed carotid neointimal formation by using balloon-injured rat carotid artery model, specifically via decreased MYADM expression, whereas adeno-miR-182-3p inhibitor significantly promoted neointimal formation. Atherosclerotic lesions from patients with high asymmetrical dimethylarginine plasma levels exhibited decreased miR-182-3p expression levels and elevated MYADM expression levels.

Conclusions—

miR-182-3p is a novel SMC phenotypic modulator by targeting
MYADM
.