bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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 &lt; 0.05 (13 down- and 87 up-regulated) and 51 metabolites changed in adenoma cases at q &lt; 0.05 (7 down- and 44 up-regulated) The most affected metabolic pathways were: fibrinogen cleavage proteins (all 3 up-regulated at q &lt; 0.05), fatty acyl carnitines (7 of 9 up-regulated at p &lt; 0.05 and 4 of 9 up-regulated at q &lt; 0.05), nucleotide sugars (6 of 9 up-regulated at p &lt; 0.05 and 3 of 9 up-regulated at q &lt; 0.05), and non-esterified long-chain unsaturated fatty acids (9 of 12 up-regulated at p &lt; 0.05 and 4 of 12 up-regulated at q &lt; 0.05). 24 metabolites differed in ΔT3-T0 between advanced adenoma cases and controls at p &lt; 0.05. The metabolic pathway most affected was fatty acyl carnitines (9 of 9 up-regulated compared to controls at p &lt; 0.10 and 5 of 9 up-regulated compared to controls at p &lt; 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

Abstract
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

Abstract
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

Abstract
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

Abstract
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&lt;0.005).
In a group of responder patients (PFS&gt;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&lt;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

Abstract
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.
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
.
Thrombus Histology Suggests Cardioembolic Cause in Cryptogenic Stroke
Authors: Boeckh-Behrens Tobias , Kleine Justus F. , Zimmer Claus , Neff Frauke , Scheipl Fabian , Pelisek Jaroslav , Schirmer Lucas , Nguyen Kim , Karatas Deniz , Poppert Holger 
Published: May 2016

Background and Purpose—
Ischemic stroke of undetermined cause is a major health issue because of its high frequency and clinical relevance. Histopathologic analysis of human thrombi, retrieved from stroke patients with large-vessel occlusion during mechanical thrombectomy, may provide information about underlying pathologies. This study examines the relationship between stroke causes and histological clot composition to identify specific patterns that might help to distinguish causes of cryptogenic stroke.

Methods—
Thrombi of 145 consecutive stroke patients with large-vessel occlusion were collected during intracranial mechanical recanalization. The hematoxylin and eosin–stained specimens were quantitatively analyzed in terms of the relative fractions of the main constituents (red and white blood cells and fibrin/platelets). These data, along with additional clinical and interventional parameters, were compared for different stroke subtypes, as defined by the international Trial of Org 10172 in Acute Stroke Treatment criteria.

Results—

The composition of thrombi from cardioembolic and noncardioembolic stroke patients differed significantly for all main thrombus components. Cardioembolic thrombi had higher proportions of fibrin/platelets (
P
=0.009), less erythrocytes (
P
=0.003), and more leucocytes (
P
=0.035) than noncardioembolic thrombi. Cryptogenic strokes showed strong overlap with cardioembolic strokes but not with noncardioembolic strokes, in terms of both thrombus histology and interventional and clinical outcome parameters.

Conclusions—
Quantitative evaluation of thrombus composition may help to distinguish between different stroke causes. Our findings support the notion that the majority of cryptogenic strokes are cardioembolic.
Orolingual Angioedema During or After Thrombolysis for Cerebral Ischemia
Authors: Myslimi Fjorda , Caparros François , Dequatre-Ponchelle Nelly , Moulin Solène , Gautier Sophie , Girardie Patrick , Cordonnier Charlotte , Bordet Régis , Leys Didier 
Published: May 2016

Background and Purpose—
Orolingual angioedema (OLAE) is a life-threatening complication of intravenous thrombolysis. Our objective was to compare outcomes of patients with and without OLAE.

Methods—
We prospectively included consecutive patients who received intravenous thrombolysis for cerebral ischemia at Lille University Hospital. We examined tongue and lips every 15 minutes during thrombolysis and ≤30 minutes after. We evaluated the 3-month outcome with the modified Rankin scale (mRS) and compared outcomes of patients with and without OLAE.

Results—

Of 923 consecutive patients, 20 (2.2%) developed OLAE. None of them needed oro-tracheal intubation. They were more likely to be under angiotensin-converting enzyme inhibitors (adjusted odds ratio [adjOR], 3.9; 95% confidence interval [CI], 1.6–9.7;
P
=0.005) to have total insular infarcts (OR, 5.0; 95% CI, 1.5–16.5;
P
=0.004) and tended to develop more symptomatic intracerebral hemorrhages. Results concerning angiotensin-converting enzyme inhibitors were not modified after adjustment for propensity scores (OR, 4.4; 95% CI, 1.6–11.9;
P
=0.004) or matched analysis based on propensity scores (OR, 3.4; 95% CI, 1.3–8.1;
P
=0.010). Patients with OLAE did not significantly differ at 3 months for the proportion of patients with mRS score of 0 to 1 (adjOR, 0.9; 95% CI, 0.3–2.1), mRS score of 0 to 2 (adjOR, 0.8; 95% CI, 0.1–1.8), and death (adjOR, 1.1; 95% CI, 0.3–3.8).

Conclusions—
OLAE occurs in 1 of 50 patients who receive intravenous thrombolysis, 1 of 10 in case of total insular infarct, and 1 of 6 if they are under angiotensin-converting enzyme inhibitors. Their long-term outcome does not differ from that of other patients.
Effects of Epinephrine Auto-Injector Shape and Size on Human Factors Influencing Drug Delivery
Authors: Barbir Ana , Janelli Mark V. , Lin Michael Y. , Dennerlein Jack T. 
Published: May 2016

Objective: The aim of this study was to assess the effects of (a) auto-injector form factor on maximum applied force capability and (b) auto-injector design and instructions on force production and orientation. Background: Effective delivery of epinephrine through an auto-injector is the result of a multitude of design factors. At minimum, the design needs to allow the user to apply sufficient force for the needle to penetrate clothing and tissue. Method: Trainer devices for three commercially available epinephrine auto-injectors with different form factors (cylindrical, elliptical, prismatic) were tested in a laboratory-based repeated-measures experiment with 20 adults. Participants applied their maximum force onto a force plate positioned over their thigh and practiced an injection using the trainer device after viewing training videos. Participants also rated force confidence and preference. Results: The maximum force varied significantly across devices. The greatest force observed was 64 newtons with the elliptical device, and the lowest force was 61 newtons with the cylindrical device. Participants reported the highest force confidence when using the elliptical and cylindrical devices, ranking the elliptical as their preferred device. Conclusion: Force capability results for the elliptical device suggest that it may be more successful in achieving the necessary force for drug delivery in a larger set of adult users. Application: Results suggest that the auto-injector with the elliptical form may enable more successful drug delivery among a larger set of users.