bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B120: Synergistic potentiation of the anti-metastatic effect of anti EGFR mAbs by its combination with immunotherapies targeting the ganglioside NGcGM3
Authors: Gonzalez Addys , Blanco Rances , Carr Adriana , Leon Kalet
Published: November 2016

Epidermal growth factor receptor (EGFR) plays an important role in cancer progression. Several anti-EGFR mAbs has demonstrated significant clinical effect in the therapy of cancer. However, their impact on patients overall survival has been limited mainly by the emergence of different forms of tumor resistance. N-glycolyl variant of GM3 ganglioside (NGcGM3) has received some attention as a privileged target for cancer therapy. This ganglioside is specifically expressed in some tumors, and it has been associated with a poor prognostic in colon and lung cancer. Several reports in the literature have documented a functional relationship between GM3 and EGFR at tumor cell membrane. GM3 physically associates to EGFR inhibiting its ligand depend phosphorylation, but it also facilitates an alternative/compensatory signaling cascade mediated by Uroquinase Plasminogen Activator Receptor (uPAR) and integrin α5β1 interaction. However, no conclusive information exists on the difference between N-glycolyl and N-Acetyl variants of GM3 regarding their interaction with EGFR and uPAR. We hypothesized that the enrichment on NGcGM3 expression in some tumors relates to advantages of this ganglioside variant, perhaps by ensuring that both EGFR and uPAR pathways optimally signal to promote tumor growth and metastasis. Following this idea, we explored the impact of a combination of immunotherapies against this two “physically or functional related targets” in the tumor. We found a clear synergistic effect of this combination in two different transplantable tumor models of lung metastasis. We show that in treated metastasis, the combination turns off more the signaling through both EGFR and uPAR/α5β1 integrin pathway and both the antibody and cellular immune response induced was important. Overall, our results support the potential combination of therapies targeting NGcGM3 with anti EGFR antibodies to increase their efficacy in future clinical trials.

Citation Format: Addys Gonzalez, Rances Blanco, Adriana Carr, Kalet Leon. Synergistic potentiation of the anti-metastatic effect of anti EGFR mAbs by its combination with immunotherapies targeting the ganglioside NGcGM3 [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B120.
Abstract B124: Roles for Tnfsf11 expression by group 3 innate lymphoid cells
Authors: Bando Jennifer K. , Song Christina , Gilfillan Susan , Colonna Marco
Published: November 2016

Innate lymphoid cells (ILC) are important sources of effector cytokines during homeostasis and diverse inflammatory conditions. A specialized group of ILC, the Group 3 ILC (ILC3), produces IL-22 and IL-17A, and contributes to maintenance of the gut epithelial barrier and the host response to extracellular microbes. ILC3s express Tnfsf11, a type II receptor required for osteoclastogenesis. The functions of Tnfsf11 in ILC3s are not fully understood. Here we show that Tnfsf11-deficient ILC3s are hyperproliferative and express altered cell surface markers at steady state. Additionally, Tnfsf11-deficient ILC3s produce increased amounts of effector cytokines in response to the activating cytokine IL-23. Although mature osteoclast-, lymph node-, and M cell-development are dysfunctional in Tnfsf11−/− mice, Tnfsf11 expression is not required in ILC3s for these developmental pathways. Thus, Tnfsf11 regulates ILC3 homeostasis in the gut.

Citation Format: Jennifer K. Bando, Christina Song, Susan Gilfillan, Marco Colonna. Roles for Tnfsf11 expression by group 3 innate lymphoid cells [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B124.
Abstract B130: Dysregulated Toll-like receptor responses as an oncogenic driver
Authors: Majer Olivia , Liu Bo , Lee Angus Yiu-fai , Barton Greg
Published: November 2016

Inflammation mediated by the transcription factor NFkB is a hallmark of many cancers. Toll-like receptor (TLR) signaling activates NFkB and many tumors undergo an upregulation of TLR expression. However, it still remains unknown to what extent TLR signaling directly contributes to tumorigenesis. A mutagenesis screen of the Unc93b1 protein, a trafficking factor for endosomal TLRs, identified numerous gain-of-function mutations that lead to enhanced TLR signaling. This system allows me to selectively upregulate the activity of certain TLRs and test their contribution to the development of spontaneous inflammation and cancer. So far, my work has focused on a group of Unc93b1 mutations that confer hyper-responsiveness of TLR7 and TLR9, two endosomal nucleic-acid sensing receptors. Knock-in mice carrying this mutation show an early onset of autoinflammation and autoimmunity, demonstrating the critical role of Unc93b1 in maintaining immunological tolerance of these receptors. In ongoing work, I want to investigate the underlying molecular mechanisms that mediate this TLR hyperresponse and identify new regulators of Unc93b1 that might engage in this pathway. Furthermore, I want to apply this system in exploring the contribution of chronic TLR7 and TLR9 stimulation in the development of B-cell lymphoma, a cancer type whose pathogenesis relies on constitutively active NFkB downstream of TLR engagement. My study will reveal novel regulatory pathways that control TLR-mediated inflammation and their physiological relevance in tumorigenesis.

Citation Format: Olivia Majer, Bo Liu, Angus Yiu-fai Lee, Greg Barton. Dysregulated Toll-like receptor responses as an oncogenic driver [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B130.
Abstract B134: Cryo-EM structure of the activated NAIP2-NLRC4 inflammasome reveals nucleated polymerization
Authors: Zhang Liman , Chen Shuobing , Ruan Jianbin , David Liron , Mao Youdong , Wu Hao
Published: November 2016

The NLR family apoptosis inhibitory proteins (NAIPs) bind conserved bacterial ligands, such as the bacterial rod protein PrgJ, and recruit NLR family CARD-containing protein 4 (NLRC4) as the inflammasome adapter to activate innate immunity. We found that the PrgJ-NAIP2-NLRC4 inflammasome is assembled into multisubunit disk-like structures through a unidirectional adenosine triphosphatase polymerization, primed with a single PrgJ-activated NAIP2 per disk. Cryo-electron microscopy (cryo-EM) reconstruction at subnanometer resolution revealed a ∼90° hinge rotation accompanying NLRC4 activation. Unlike in the related heptameric Apaf-1 apoptosome, in which each subunit needs to be conformationally activated by its ligand before assembly, a single PrgJ-activated NAIP2 initiates NLRC4 polymerization in a domino-like reaction to promote the disk assembly. These insights reveal the mechanism of signal amplification in NAIP-NLRC4 inflammasomes.

Citation Format: Liman Zhang, Shuobing Chen, Jianbin Ruan, Liron David, Youdong Mao, Hao Wu. Cryo-EM structure of the activated NAIP2-NLRC4 inflammasome reveals nucleated polymerization [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B134.
Abstract B135: Chemotherapy for esophageal cancer: Off-target effect and biomarker
Authors: Takeoka Tomohira , Goto Kumiko , Matsumoto Mitsunobu , Miyazaki Yasuhiro , Makino Tomoki , Takahashi Tsuyoshi , Kurokawa Yukinori , Yamasaki Makoto , Takiguchi Shuji , Mori Masaki , Doki Yuichiro , Wada Hisashi
Published: November 2016

Background/Purpose: For esophageal cancer patients, combination chemotherapy with docetaxel, cisplatin, and 5FU (DCF therapy) is adopted for neoadjuvant chemotherapy (NAC). Although the response rate is high (72.5%), further investigation of indicators to predict its therapeutic effects is needed because of its side effects, and few have been reported. In this study, we obtained peripheral blood before and after the DCF therapy, analyzed various immune related cells by flow cytometry and tried to identify indicators to predict its therapeutic effects.

Subjects/Methods: Peripheral blood were obtained from 20 esophageal cancer patients before and after preoperative DCF therapy. During two cycles of one-week-on and three-week-off administration, peripheral blood was collected before and after each “on” and before and after the surgical treatment followed by. By flow cytometry, CD15+CD14− granulocytes and CD15−CD14+ monocytes were observed. The effectiveness of NAC was determined hisitopathologically in accordance with the grading system of the Japanese Classification of Esophageal Carcinoma. Grading was as follows: Grade 0, no part of the tumor was affected; Grade1, less than two-thirds of the tumor was affected; Grade2, between two-thirds and the entire tumor was affected; and Grade 3, no residual tumor was present (Pathologically complete response) and clinically RECIST. Then their association were analyzed.

Results/Discussion: Of 20 patients with esophageal cancer, 13 patients were responders and 7 patients were non-responders to the DCF therapy. Just after the first “on” course, the ratio of monocytes to myelocytes was observed in 25.4 ± 32.0% in the non-responders and 7.8 ± 10.3% in the responders (p = 0.073). The numbers of monocytes calculated were 229.4 ± 212.2 /μL in the non-responders and 51.1 ± 71.1 /μL in the responders (p = 0.01). Patients with better pathological or clinical responses showed lower ratio of monocytes to myelocytes and fewer number of monocytes in peripheral blood. No relationship was observed between granulocytes and the therapeutic response.

Conclusion: These results suggest that analyzing immune related cells in peripheral blood might be useful for identification of predictive indicators for the response of preoperative DCF therapy.

Citation Format: Tomohira Takeoka, Kumiko Goto, Mitsunobu Matsumoto, Yasuhiro Miyazaki, Tomoki Makino, Tsuyoshi Takahashi, Yukinori Kurokawa, Makoto Yamasaki, Shuji Takiguchi, Masaki Mori, Yuichiro Doki, Hisashi Wada. Chemotherapy for esophageal cancer: Off-target effect and biomarker [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B135.
Abstract IA15: Microbiota and cancer immunosurveillance: An introduction
Authors: Kroemer Guido
Published: November 2016

Anticancer immune responses can be considered a desirable form of autoimmunity that may be profoundly shaped by the microbiome. Such anticancer immune responses may occur as part of the natural immunosurveillance system as well as a result of therapeutic interventions including chemotherapy, radiotherapy, and immuotherapy. I will discuss evidence for the microbiome's influence on antitumor immunosurveillance, including those that are indirect and can act at a distance. I will put forward hypotheses regarding mechanisms of how these effects are implemented. These may involve cross-reactivity between microbial and tumor antigens shaping T cell repertoires and/or microbial products stimulating pattern recognition receptors that influence the type and intensity of immune responses. Understanding how the microbiome impacts natural cancer immunosurveillance as well as treatment-induced immune responses will pave the way for more effective therapies and prophylactics.

References

1. Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G. Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. Cancer Cell 2015;28(6):690-714.

2. Pietrocola F, Pol J, Vacchelli E, Rao S, Enot DP, Baracco EE, Levesque S,Castoldi F, Jacquelot N, Yamazaki T, Senovilla L, Marino G, Aranda F, Durand S, Sica V, Chery A, Lachkar S, Sigl V, Bloy N, Buque A, Falzoni S, Ryffel B, Apetoh L, Di Virgilio F, Madeo F, Maiuri MC, Zitvogel L, Levine B, Penninger JM, Kroemer G. Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance. Cancer Cell 2016;30(1):147-60.

3. Zitvogel L, Ayyoub M, Routy B, Kroemer G. Microbiome and Anticancer Immunosurveillance. Cell 2016;165(2):276-87.

Citation Format: Guido Kroemer. Microbiota and cancer immunosurveillance: An introduction [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA15.
Abstract IA26: Combinatorial immunotherapies with the potential to reverse the carcinogenesis process
Authors: Jaffee Elizabeth M.
Published: November 2016

Until recently, barriers to immunotherapy clinical successes for pancreatic cancer have been due to a lack of understanding of the immune pathways within the pancreatic tumor microenvironment that hinder successful immune responses. Recent advances have identified new targets for developing cancer specific vaccines and new targets for modulating the tumor microenvironment to allow more potent activation and improved access of vaccine induced immune responses. We are just learning that non-neoplastic cells, including cancer-associated myofibroblasts, regulatory T cells, dendritic cells, myeloid-derived suppressor cells, and tumor-associated macrophages, are hijacked by pre-invasive and invasive cancer cells to create a tolerogenic tumor microenvironment. Current research is focused on elucidating the mechanisms of this tolerogenic polarization within the tumor microenvironment with the goal of tipping the balance in favor of an anticancer immune response. With the recent advances in molecular technologies and the development of relevant pancreatic cancer mouse models, it is now within our reach to dissect the inhibitory pathways within the pancreatic tumor microenvironment. This will in turn, lead to new therapeutic opportunities that will eliminate these barriers and convert this deadly cancer into a treatable disease.

References

1. Keenan et al. A Listeria vaccine and depletion of Tregs activate immunity against early pancreatic intraepithelial neoplasms and prolong the survival of mice. Gastronterology 2014;146:1784-994.

2. Lutz et al. Immunotherapy converts nonimmunogenic pancreatic tumors into foci of immune regulation. Cancer Immunology Research 2014; 2(7):616-31.

3. Kouo et al. Galectin-3 shapes antitumor immune responses by suppressing CD8+ T cells via LAG-3 and inhibiting expansion of plasmacytoid dendritic cells. Cancer Immunology Research 2015;3(4):412-23.

[Supported by grants from the National Cancer Institute, National Institutes of Health (P50CA062924, R01CA122081, P30CA006973, and U19CA113341 to E.M.J.), and supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer.]

Citation Format: Elizabeth M. Jaffee. Combinatorial immunotherapies with the potential to reverse the carcinogenesis process [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA26.
Abstract PR02: A personalized neoantigen vaccine in patients with high risk melanoma
Authors: Ott Patrick A. , Hu Zhuting , Keskin Derin B. , Shukla Sachet A. , Sun Jing , Fritsch Ed , Hacohen Nir , Wu Catherine J.
Published: November 2016

Neoantigens arise from somatic tumor mutations and can encode amino acid changes, generating peptides with the potential to bind to HLA molecules. Since these neoepitopes provide exquisite tumor specificity and are expected to be highly immunogenic as they are not subject to central tolerance, they were long-envisioned as highly valuable tumor antigens. Growing evidence has supported tumor neoepitopes as key antigens triggering immune-mediated tumor killing in vivo across settings of effective cancer immunotherapy, including checkpoint blockade and adoptive transfer with tumor-infiltrating lymphocytes. Vaccination is a potentially effective approach for inducing tumor-specific immune responses, but has been limited by the lack of a sufficiently potent vaccine immunogen. By leveraging next-generation sequencing technologies and new analytical pipelines to systematically identify personal tumor neoantigens, in a phase 1 trial we tested the feasibility, safety, and immunogenicity of a multi-epitope cancer vaccine targeting personal tumor neoantigens in patients with high-risk melanoma. Mutations were identified by DNA and RNA sequencing; epitopes were selected based on class I HLA binding prediction algorithms. The vaccines, comprised of up to 20 long peptides spanning mutated tumor epitopes and admixed with the Toll-Like Receptor 3 agonist poly-ICLC, were administered using a prime-boost approach. Of 12 patients enrolled, the initial 6 patients who received the full set of priming and booster vaccinations experienced only minimal adverse events, consisting of mild and transient injection site reaction, flu-like symptoms, and rash. We identified strong, polyfunctional CD4+ and CD8+ T cell responses against multiple neoepitopes in all dosed patients. Processing and presentation of neoantigens on autologous tumors was confirmed by mass spectrometry and recognition of autologous tumor by vaccine-induced neoantigen-specific T cells was verified. These studies show that a personalized neoantigen vaccine is safe, feasible, and strongly immunogenic in cancer patients. The data should reinvigorate the field of cancer vaccines, providing a rational path for the building of combinatorial approaches to extend their efficacy.

Citation Format: Patrick A. Ott, Zhuting Hu, Derin B. Keskin, Sachet A. Shukla, Jing Sun, Ed Fritsch, Nir Hacohen, Catherine J. Wu. A personalized neoantigen vaccine in patients with high risk melanoma [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr PR02.
Abstract PR15: Engineering phagocytic signaling
Authors: Williamson Adam , Vale Ron
Published: November 2016

Phagocytosis of specific targets in clinically-relevant settings, including engulfment of tumor cells and removal of cell corpses following aggressive cancer treatment, has been hampered by an incomplete understanding of phagocytic signaling. Therefore, we developed a cellular reconstitution platform amenable to direct, real-time imaging to dissect phagocytic signaling in molecular detail. Our gain-of-function system converts inept phagocytes into efficient ones, enabling us to appreciate the signaling behaviors associated with phagocytic proficiency. We report that 1) phagocytosis receptors form mobile microclusters in response to ligation, 2) microclusters recruit cytosolic collaborators to the plasma membrane and spatially organize actin dynamics at the phagocytic synapse, and 3) the natural ligand-receptor pair can be replaced by an engineered module, indicating that phagocytic signaling can be reprogrammed towards specific targets. Thus, we have discovered that a conserved signaling system required for recognition and removal of altered self bears unexpected mechanistic similarity to adaptive immune responses directed towards pathogens and tumor cells. In addition, our ability to replace the endogenous receptor with a heterologous system indicates that phagocytosis can be programmed in a manner conceptually similar to the Chimeric Antigen Receptor used in the clinic to program cytotoxic T cells to kill tumor cells. Our ability to engineer the process suggests that methods to re-direct phagocytes towards targets of clinical importance are possible, approaches that may enable recognition and removal of tumor cells and boost the anti-tumor immune response.

Citation Format: Adam Williamson, Ron Vale. Engineering phagocytic signaling [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr PR15.
Metabolic Stress Induces Caspase-3 Mediated Degradation and Inactivation of Farnesyl and Geranylgeranyl Transferase Activities in Pancreatic β-Cells
Authors: Veluthakal Rajakrishnan , Arora Daleep K. , Goalstone Marc L. , Kowluru Renu A. , Kowluru Anjaneyulu
Published: November 2016

Background/Aims: At least 300 prenylated proteins are identified in the human genome; the majority of which partake in a variety of cellular processes including growth, differentiation, cytoskeletal organization/dynamics and vesicle trafficking. Aberrant prenylation of proteins is implicated in human pathologies including cancer; neurodegenerative diseases, retinitis pigmentosa, and premature ageing syndromes. Original observations from our laboratory have demonstrated that prenylation of proteins [small G-proteins and γ-subunits of trimeric G-proteins] is requisite for physiological insulin secretion. Herein, we assessed the impact of metabolic stress [gluco-, lipotoxicity and ER-stress] on the functional status of protein prenylation pathway in pancreatic β-cells. Methods: Farnesyltransferase [FTase] and geranylgeranyltransferase [GGTase] activities were quantified by radioisotopic methods. Caspase-3 activation and FTase/GGTase-α subunit degradation were determined by Western blotting. Results: We observed that metabolic stress activates caspase-3 and induces degradation of the common α-subunit of FTase and GGTase-I in INS-1 832/13 cells, normal rodent islets and human islets leading to functional defects [inactivation] in FTase and GGTase activities. Caspase-3 activation and FTase/GGTase-α degradation were also seen in islets from the Zucker diabetic fatty [ZDF] rat, a model for Type 2 diabetes. Consequential to defects in FTase/GGTase-α signaling, we observed significant accumulation of unprenylated proteins [Rap1] in β-cells exposed to glucotoxic conditions. These findings were replicated in β-cells following pharmacological inhibition of generation of prenylpyrophosphate substrates [Simvastatin] or catalytic activity of prenylating enzymes [GGTI-2147]. Conclusions: Our findings provide the first evidence to suggest that metabolic stress induced dysfunction of the islet β-cell may, in part, be due to defective protein prenylation signaling pathway.
WIN 55,212-2 Inhibits the Epithelial Mesenchymal Transition of Gastric Cancer Cells via COX-2 Signals
Authors: Xian Xiangshu , Huang Liuye , Zhang Bo , Wu Chengrong , Cui Jun , Wang Zhihua
Published: November 2016

Background: Cannabinoids (the active components of Cannabis sativa) and their derivatives have received considerable interest due to reports that they can affect the tumor growth, migration, and metastasis. Previous studies showed that the cannabinoid agonist WIN 55,212-2 (WIN) was associated with gastric cancer (GC) metastasis, but the mechanisms were unknown. Methods: The effects of WIN on GC cell migration and invasion were analyzed by the wound-healing assay and Transwell assay. Quantitative real-time PCR and Western blot were used to evaluate changes in expression of COX-2 and EMT associated markers in SGC7901 and AGS cells. Results: WIN inhibited cell migration, invasion, and epithelial to mesenchymal transition (EMT) in GC. WIN treatment resulted in the downregulation of cyclooxygenase-2 (COX-2) expression and decreased the phosphorylation of AKT, and inhibited EMT in SGC7901 cells. Decreased expression of COX-2 and vimentin, and increased expression of E-cadherin, which was induced by WIN, were normalized by overexpression of AKT, suggesting that AKT mediated, at least partially, the WIN suppressed EMT of GC cells. Conclusion: WIN can inhibit the EMT of GC cells through the downregulation of COX-2.
Kappa-Opioid Agonist U50,488H-Mediated Protection Against Heart Failure Following Myocardial Ischemia/Reperfusion: Dual Roles of Heme Oxygenase-1
Authors: Tong Guang , Zhang Ben , Zhou Xuan , Zhao Jinbo , Sun Zhongchan , Tao Ye , Pei Jianming , Zhang Weida
Published: November 2016

Backgrounds/Aims: The selective κ-opioid agonist U50,488H protects heart from myocardial ischemia-reperfusion (MI/R) injury. We examined whether U50,488H is also beneficial for MI/R induced heart failure. Methods: Anesthetized male Sprague-Dawley rats were subjected to 30 min of myocardial ischemia via left anterior descending coronary artery (LAD) occlusion, followed by 4 weeks of reperfusion. Infarct size was examined by Evans blue/triphenyl tetrazolium chloride (TTC) staining. Cardiac function and remodeling were examined by echocardiography and histology. HO-1 gene transcription and expression were measured by RT-PCR and western blot. Results: Compared to vehicle-treated MI/R rats, rats administered a single dose of U50,488H at the beginning of reperfusion exhibited reduced myocardial infarct size, oxidative stress, hypertrophy, and fibrosis, improved mechanical function, and greater neovascularization. U50,488H also increased myocardial heme oxygenase (HO)-1 gene transcription and expression, while pharmacological HO-1 inhibition reversed all protective effects of U50,488H. Furthermore, U50,488H protected control cultured cardiomyoctes against simulated I/R-induced apoptosis but not cultures subjected to shRNA-mediated HO-1 knockdown. Inhibition of HO-1 in the subacute phase of reperfusion reversed the U50,488H-induced increase in neovascularization and suppression of oxidative stress. Finally, U50,488H increased Akt phosphorylation and nuclear translocation of Nrf2, a key HO-1 transcription activator, while inhibition of PI3K-Akt signaling abolished U50,488H-induced Nrf2 nuclear translocation, HO-1 upregulation, and cardioprotection. Conclusion: Activation of HO-1 expression through the PI3K-Akt-Nrf2 pathway may mediate the acute and long-term protective effects of U50,488H against heart failure by enhancing cardiomyocyte survival and neoangiogenesis and by reducing oxidative stress.
Valproic Acid Promotes Human Glioma U87 Cells Apoptosis and Inhibits Glycogen Synthase Kinase-3β Through ERK/Akt Signaling
Authors: Zhang Chi , Liu Songlin , Yuan Xianrui , Hu Zhongliang , Li Haoyu , Wu Ming , Yuan Jian , Zhao Zijin , Su Jun , Wang Xiangyu , Liao Yiwei , Liu Qing
Published: November 2016

Background: Valproic acid (VPA), an established antiepileptic drug, was assessed for antitumor activity, including its effects on glioblastoma, but its role has not been determined. Methods: In the present study, we investigated VPA-induced apoptosis effects on human U87 cells by cell viability, lactate dehydrogenase (LDH) release, TUNEL/Hoechst staining and flow cytometric in vitro, then we further explored the underlying molecular mechanisms using the selective antagonists PD98059, LY294002 and SB216763. Results: The data showed that VPA dose-dependent induction of glioma U87 cells to undergo apoptosis through the mitochondria-dependent pathway in vitro. VPA activated the ERK/Akt pathways by increasing their protein phosphorylation and in turn inhibited GKS3β activation by the induction of GKS3β phosphorylation. However, the MAPK inhibitor PD98059 and/or PI3K inhibitor LY294002 were able to antagonize the effects of VPA by abolishing ERK/Akt activations and cancelling GSK3β suppression, thus it impaired VPA apoptosis-inducing effects on glioma cells. Furthermore, the GSK3β inhibitor SB216763 caused a strong suppression of GSK3β activity, which showed similar effects of VPA on regulation of protein expression and apoptosis. Conclusion: These findings suggest that GSK3β may be the central hub for VPA-induced apoptosis and VPA can be further evaluated as a novel agent for glioma therapy.
Characterization of the Anticoagulant and Antithrombotic Properties of the Sphingosine 1-Phosphate Mimetic FTY720
Authors: Zhao Zhen , Wang Ruixue , Huo Zhijun , Li Chunlei , Wang Zhiyong
Published: November 2016

Sphingosine 1-phosphate (S1P) is a highly active lysophospholipid implicated in various cardiocerebrovascular events such as coagulation, myocardial infarction and stroke. However, as the functional S1P receptor antagonist, whether the S1P mimetic FTY720 can modulate coagulation and/or thrombotic formation remains largely unknown. We investigated the effects of FTY720 on adenosine diphosphate (ADP)-induced platelet aggregation, coagulation parameters and thrombus formation in rats. Pretreatment with FTY720 (2.5 mg/kg) inhibited platelet aggregation induced by ADP, elongated the thrombin time and decreased the fibrinogen levels. However, FTY720 produced no significant effects on the arteriovenous bypass thrombus formation or the FeCl3-induced thrombus formation in the inferior vena cava and the common carotid artery. Our data suggest that FTY720 can exert an inhibitory effect on platelet aggregation and coagulation-related parameters. These characteristics of FTY720 could be useful as an adjunct in the treatment of ischemic diseases such as ischemic stroke and myocardial infarction.
Encephalography Connectivity on Sources in Male Nonsmokers after Nicotine Administration during the Resting State
Authors: Ranzi Paolo , Freund Jan A. , Thiel Christiane M. , Herrmann Christoph S.
Published: November 2016

We present an encephalography (EEG) connectivity study where 30 healthy male nonsmokers were randomly allocated either to a nicotine group (14 subjects, 7 mg of transdermal nicotine) or to a placebo group. EEG activity was recorded in an eyes-open (EO) and eyes-closed (EC) condition before and after drug administration. This is a reanalysis of a previous dataset. Through a source reconstruction procedure, we extracted 13 time series representing 13 sources belonging to a resting-state network. Here, we conducted connectivity analysis (renormalized partial directed coherence; rPDC) on sources, focusing on the frequency range of 8.5-18.4 Hz, subdivided into 3 frequency bands (α1, α2, and β1) with the hypothesis that an increase in vigilance would modulate connectivity. Furthermore, a phase-amplitude coupling (mean resultant vector length; VL) analysis, was performed investigating whether an increase of vigilance would modulate phase-amplitude coupling. In the VL analysis we estimated the coupling of the phases of 3 low frequencies (α1, α2, and β1), respectively, with the amplitude of high-frequency oscillations (30-40 Hz, low γ). With rPDC we found that during the EC condition, nicotine decreased feedback connectivity (from the precentral gyrus to precuneus, angular gyrus, cuneus and superior occipital gyrus) at 10.5-12.4 Hz. The VL analysis showed nicotine-induced increases in coupling at 10.5-18.4 Hz in the precuneus, cuneus and superior occipital gyrus during the EC condition. During the EO condition, no significant results were found in connectivity or phase-amplitude coupling measures at any frequency range. In conclusion, the results suggest that nicotine potentially increases the level of vigilance in the EC condition.
A Review of DNA Methylation and microRNA Expression in Recurrent Pediatric Acute Leukemia
Authors: Hale Victoria , Hale Gregory A. , Brown Patrick A. , Amankwah Ernest K.
Published: November 2016

Acute leukemia is the most common childhood cancer diagnosis and leading cause of cancer-related death among children and adolescents. Despite substantial improvements in the survival rate of childhood acute leukemia, approximately 20-40% of the patients who undergo treatment develop relapse, with a dismal one third of these patients surviving in the long term. Epigenetics plays an important role in the progression of cancer, and existing evidence suggests a role in childhood acute leukemia relapse. A better understanding of the epigenetic mechanisms in recurrent acute leukemia could potentially lead to novel therapeutic regimens to prevent or treat disease recurrences. In this review, we summarize existing evidence on two of the most studied epigenetic mechanisms, DNA methylation and microRNA expression, in recurrent pediatric acute leukemia.
Risk Factors of Hyphema following Surgeries for Primary Rhegmatogenous Retinal Detachment
Authors: Kung Ya-Hsin , Wu Tsung-Tien
Published: November 2016

Purpose: This study aimed to evaluate the risk factors for hyphema complicating primary rhegmatogenous retinal detachment (RRD) surgeries and to analyze outcomes. Methods: In this retrospective comparative study, we included 1,011 consecutive eyes. Two groups were compared according to the occurrence of postoperative hyphema. Results: Postoperative hyphema occurred in 32 eyes (3.17%). High myopia was significantly related to the occurrence of hyphema (odds ratio [OR] 3.396, 95% confidence interval [CI] 1.502-7.675; p = 0.003). Combined scleral buckling and vitrectomy (SB + VT) was associated with a significantly higher incidence of hyphema (OR 21.266, 95% CI 4.855-93.152; p < 0.001). The final anatomical success rate did not differ significantly between the group with and the group without occurrence of hyphema; however, the primary anatomical success rate was worse in the eyes with hyphema. Conclusions: High myopia and combined SB + VT were risk factors for hyphema after RRD surgeries. The occurrence of hyphema did not affect the final anatomical success rate at 6 months.
Giant true Brachial Artery Aneurysm after Hemodialysis Fistula Closure in a Renal Transplant Patient
Authors: Ferrara Doriana , Di Filippo Michele , Spalla Flavia , Giribono Anna Maria , Viviani Emanuela , Santagata Annamaria , Bracale Umberto , Santangelo Michele , del Guercio Luca , Bracale Umberto Marcello
Published: November 2016

The usual manifestation of brachial artery aneurysms is the incidental finding of a swelling of the arm, combined with paresthesia or pain in some cases. The etiology is often traumatic or secondary to drug abuse. Pathophysiology of brachial artery dilation in these cases is not completely clear. We herein describe a case of a 61-year-old male presenting with a giant, painful, pulsatile mass on his left arm. He was submitted to a cadaveric kidney transplant in 2005. He had a functioning arteriovenous fistula (AVF) on his right arm, and a spontaneously thrombosed radiocephalic AVF on his left arm. The aneurysm was surgically resected, sparing the median nerve that was totally entrapped and an inverted segment of the basilic vein interposed. At the follow-up, the patient did not present neurological or ischemic disturbs, and the vein graft maintained its patency.
Choroidal Metastasis as an Unusual Initial Presentation of Transitional Cell Carcinoma of the Kidney
Authors: Khader Jamal , Mheid Sara , AbuHijla Fawzi , AlKarmi Nadi , Yousef Yacoub , Othman Yazan
Published: November 2016

Metastases of transitional cell carcinoma (TCC) of the renal pelvis to the eye is a very rare event, as only one previous case has been described in the literature. We present a patient with choroidal metastasis secondary to TCC of the renal pelvis, with a review of the relevant literature. A 61-year-old male presented with sudden-onset loss of vision of the left eye. Upon evaluation and assessment, the patient was found to have unilateral choroidal metastasis secondary to TCC of the renal pelvis. He is currently on palliative chemotherapy with carboplatin and gemcitabine. External beam radiation therapy is a common mode of treatment and will be considered accordingly.
Nationwide Study of the Treatment of Mycotic Abdominal Aortic Aneurysms Comparing Open and Endovascular Repair
Authors: Sörelius Karl , Wanhainen Anders , Furebring Mia , Björck Martin , Gillgren Peter , Mani Kevin , Lindström David , Hultgren Rebecka , Wahlgren Carl-Magnus , Roos Håkan , Langenskiöld Marcus , Resch Timothy , Vaccarino Roberta , Bilos Linda , Pirouzram Artai , Arnerlöv Conny , Simo Gabor , Svensson Mats , Magnusson Johan , Astrand Håkan , Gilgen Nils-Peter , Mellander Stefan , Korman David , Djavani-Gidlund Khatereh , Palm Markus , Huss Mårten , Bertszel Adam , Docter Michael , Drott Christer , Öjersjö Andreas , Nelzén Olle , Wetterling Tomas , Chu Ming
Published: November 2016

Background:

No reliable comparative data exist between open repair (OR) and endovascular aneurysm repair (EVAR) for mycotic abdominal aortic aneurysms (MAAAs). This nationwide study assessed outcomes after OR and EVAR for MAAA in a population-based cohort.

Methods:

All patients treated for MAAAs in Sweden between 1994 and 2014 were identified in the Swedish vascular registry. The primary aim was to assess survival after MAAA with OR and EVAR. Secondary aims were analyses of the rate of recurrent infections and reoperations, and time trends in surgical treatment. Survival was analyzed using Kaplan-Meier and log-rank tests. A propensity score–weighted correction for risk factor differences in the 2 groups was performed, including the operation year to account for differences in treatment and outcomes over time.

Results:

We identified 132 patients (0.6% of all operated abdominal aortic aneurysms in Sweden). Mean age was 70 years (standard deviation, 9.2), and 50 presented with rupture. Survival at 3 months was 86% (95% confidence interval, 80%–92%), at 1 year 79% (72%–86%), and at 5 years 59% (50%–68%). The preferred operative technique shifted from OR to EVAR after 2001 (proportion EVAR 1994–2000 0%, 2001–2007 58%, 2008–2014 60%). Open repair was performed in 62 patients (47%): aortic resection and extra-anatomic bypass (n=7), in situ reconstruction (n=50), and patch plasty (n=3); 2 patients died intraoperatively. EVAR was performed in 70 patients (53%): standard EVAR (n=55), fenestrated/branched EVAR (n=8), and visceral deviation with stent grafting (n=7); no deaths occurred intraoperatively. Survival at 3 months was lower for OR than for EVAR (74% versus 96%,
P
<0.001), with a similar trend present at 1 year (73% versus 84%,
P
=0.054). A propensity score–weighted risk-adjusted analysis confirmed the early better survival associated with EVAR. During median follow-up of 36 and 41 months for OR and EVAR, respectively, there was no difference in long-term survival (5 years 60% versus 58%,
P
=0.771), infection-related complications (18% versus 24%,
P
=0.439), or reoperation (21% versus 24%,
P
=0.650).

Conclusion:

This study demonstrates a paradigm shift in treatment of MAAA in Sweden, with EVAR being the preferred treatment modality. EVAR was associated with improved short-term survival in comparison with OR, without higher associated incidence of serious infection-related complications or reoperations.
Modulating Vascular Hemodynamics With an Alpha Globin Mimetic Peptide (HbαX)
Authors: Keller T.C. Stevenson , Butcher Joshua T. , Broseghini-Filho Gilson Brás , Marziano Corina , DeLalio Leon J. , Rogers Stephen , Ning Bo , Martin Jennifer N. , Chechova Sylvia , Cabot Maya , Shu Xiahong , Best Angela K. , Good Miranda E. , Simão Padilha Alessandra , Purdy Michael , Yeager Mark , Peirce Shayn M. , Hu Song , Doctor Allan , Barrett Eugene , Le Thu H. , Columbus Linda , Isakson Brant E.
Published: November 2016

The ability of hemoglobin to scavenge the potent vasodilator nitric oxide (NO) in the blood has been well established as a mechanism of vascular tone homeostasis. In endothelial cells, the alpha chain of hemoglobin (hereafter, alpha globin) and endothelial NO synthase form a macromolecular complex, providing a sink for NO directly adjacent to the production source. We have developed an alpha globin mimetic peptide (named HbαX) that displaces endogenous alpha globin and increases bioavailable NO for vasodilation. Here we show that, in vivo, HbαX administration increases capillary oxygenation and blood flow in arterioles acutely and produces a sustained decrease in systolic blood pressure in normal and angiotensin II–induced hypertensive states. HbαX acts with high specificity and affinity to endothelial NO synthase, without toxicity to liver and kidney and no effect on p50 of O
2
binding in red blood cells. In human vasculature, HbαX blunts vasoconstrictive response to cumulative doses of phenylephrine, a potent constricting agent. By binding to endothelial NO synthase and displacing endogenous alpha globin, HbαX modulates important metrics of vascular function, increasing vasodilation and flow in the resistance vasculature.
Clopidogrel Improves Skin Microcirculatory Endothelial Function in Persons With Heightened Platelet Aggregation
Authors: Salimi Shabnam , Lewis Joshua P. , Yerges‐Armstrong Laura M. , Mitchell Braxton D. , Saeed Faisal , O'Connell Jeffry R. , Perry James A. , Ryan Kathleen A. , Shuldiner Alan R. , Parsa Afshin
Published: November 2016

Background

Platelet activation can lead to enhanced oxidative stress, inflammatory response, and endothelial dysfunction. To quantify the effects of platelet inhibition on endothelial function, we assessed platelet activity of healthy persons before and after clopidogrel administration and evaluated its effects on endothelial function. We hypothesized that clopidogrel, by attenuating platelet activity, would result in enhanced endothelial function.

Methods and Results

Microcirculatory endothelial function was quantified by laser Doppler flowmetry (
LDF
) mediated by thermal hyperemia (
TH
) and postocclusive reactive hyperemia, respectively, in 287 and 241 relatively healthy and homogenous Old Order Amish persons.
LDF
and platelet aggregation measures were obtained at baseline and after 7 days of clopidogrel administration. Our primary outcome was percentage change in post‐ versus preclopidogrel
LDF
measures. Preclopidogrel
TH
‐
LDF
and platelet aggregation were higher in women than in men (
P
<0.001). Clopidogrel administration was associated with ≈2‐fold higher percentage change in
TH
‐
LDF
in participants with high versus low baseline platelet aggregation (39.4±10.1% versus 17.4±5.6%,
P
=0.03). Clopidogrel also increased absolute
TH
‐
LDF
measures in persons with high platelet aggregation (1757±766 to 2154±1055,
P
=0.03), with a more prominent effect in women (1909±846 to 2518±1048,
P
=0.001). There was no evidence that clopidogrel influenced postocclusive reactive hyperemia
LDF
measures.

Conclusions

The administration of clopidogrel in healthy persons with high baseline platelet aggregation results in improved
TH
‐induced microcirculatory endothelial function. These data suggest that clopidogrel may have a beneficial effect on microcirculatory endothelial function, presumably through antiplatelet activity, and may confer additional vascular benefits.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov
. Unique identifier:
NCT
00799396.
Effects of Statin on Arrhythmia and Heart Rate Variability in Healthy Persons With 48‐Hour Sleep Deprivation
Authors: Chen Wei Ren , Liu Hong Bin , Sha Yuan , Shi Yang , Wang Hao , Yin Da Wei , Chen Yun Dai , Shi Xiang Min
Published: November 2016

Background

It has been reported that sleep deprivation is associated with cardiac autonomic disorder, inflammation, and oxidative stress. Statins have significant cardiovascular protective effects in patients with cardiovascular disease. This study aimed to investigate the protective effect of statins on arrhythmia and heart rate variability in young healthy persons after 48‐hour sleep deprivation.

Methods and Results

This study enrolled 72 young healthy participants aged 26.5±3.5 years. All participants received 48‐hour continuous ambulatory electrocardiogram monitoring. Arrhythmia, time, and frequency domain parameters were analyzed for all participants. The primary end point, low/high frequency ratio, was significantly lower in the statin group than in the control group (2.48±1.12 versus 3.02±1.23,
P
<0.001). After 48‐hour sleep deprivation, low frequency—the frequency of premature atrial complexes and premature ventricular complexes—was significantly decreased in the statin group compared with the control group (
P<
0.05). There was also a significant increase in high frequency in the statin group compared with the control group (
P<
0.05). There was a significant decrease in serum high‐sensitivity C‐reactive protein and malondialdehyde levels after 48‐hour sleep deprivation in the statin group compared with the control group (
P
<0.05).

Conclusions

Statin use might be associated with improvement in arrhythmia and heart rate variability in healthy persons with 48‐hour sleep deprivation. This finding should be confirmed by larger scale trials.

Clinical Trial Registration

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT02496962.
Domesticating Viragos. The Politics of Womanhood in the Romanian Legionary Movement
Authors: Rusu Mihai Stelian
Published: November 2016

Building on the basic premise that the attempt to create a New Man was one of fascism’s master-ideas, this article focuses on the feminine underside of this program of political anthropogenesis. The article centers on the image of the New Woman and the politics of womanhood within the Romanian Legionary movement. It argues that the Legion’s trademark rhetoric of martial heroism and martyrdom led to an essential tension between a virile model of womanhood (patterned upon the masculine ideal type of the martyr-hero) and a more conservative domestic model. A third, reconciliatory hybrid model, which mixed features borrowed from the two antagonistic types of Legionary womanhood was eventually developed to defuse this tension.
Louis Hamilton: A British Scholar in Nazi Germany
Authors: Grams Grant W.
Published: November 2016

Louis Hamilton (1879–1948) was a British national that lectured at various institutions of higher learning in Berlin from 1904–1914, and 1919–1938. During the Third Reich (1933–1945) Hamilton was accused of being half-Jewish and his continued presence at institutions of higher learning was considered undesirable. Hamilton like other foreign born academics was coerced to leave Germany because the Nazi educational system viewed them as being politically unreliable. Hamilton’s experiences are an illustration of what foreign academics suffered during the Third Reich. The purpose of this article is to shed new light on the fate of foreign academics in Nazi Germany. Although the fate of Jewish professors and students has been researched non-Jewish and non-Aryan instructors has been a neglected topic within the history of Nazism.
Fordiophyton zhuangiae (Melastomataceae), a new species from China based on morphological and molecular evidence
Authors: ZENG SI-JIN , HUANG GE-HAN , LIU QIANG , YAN XIAO-KAI , ZHANG GUO-QIANG , TANG GUANG-DA
Published: November 2016

Historically, the taxonomic study of the Asian genus Fordiophyton has had some gaps. Several specimens from Guangdong (China) have been misidentified as Fordiophyton brevicaule C. Chen. The new species proposed here shares with F. brevicaule the densely hirsute stem, rosetted leaves and glabrous hypanthia, but it is distinguished by its glabrous leaves, winged petioles, oblong petals lacking a single trichome at the apex, and purplish anthers in the longer set of stamens. The phylogenetic analyses indicate that it is a member of Fordiophyton and sister to F. brevicaule. Based on morphological and molecular data, we here recognize it as a new species, Fordiophyton zhuangiae S. Jin Zeng & G. D. Tang, which is described and illustrated.