bluuebunny/crossref_metadata_2025 huggingface dataset:
The Microbiome in Connective Tissue Diseases and Vasculitides: An Updated Narrative Review
Authors: Talotta Rossella , Atzeni Fabiola , Ditto Maria Chiara , Gerardi Maria Chiara , Sarzi-Puttini Piercarlo
Published: August 2017

Objective. To provide a narrative review of the most recent data concerning the involvement of the microbiome in the pathogenesis of connective tissue diseases (CTDs) and vasculitides.Methods. The PubMed database was searched for articles using combinations of words or terms that included systemic lupus erythematosus, systemic sclerosis, autoimmune myositis, Sjögren’s syndrome, undifferentiated and mixed CTD, vasculitis, microbiota, microbiome, and dysbiosis. Papers from the reference lists of the articles and book chapters were reviewed, and relevant publications were identified. Abstracts and articles written in languages other than English were excluded.Results.We found some evidence that dysbiosis participates in the pathogenesis of systemic lupus erythematosus, systemic sclerosis, Sjögren’s syndrome, and Behçet’s disease, but there are still few data concerning the role of dysbiosis in other CTDs or vasculitides.Conclusions.Numerous studies suggest that alterations in human microbiota may be involved in the pathogenesis of inflammatory arthritides as a result of the aberrant activation of the innate and adaptive immune responses. Only a few studies have explored the involvement of dysbiosis in other CTDs or vasculitides, and further research is needed.
Effects of Geometry Design Parameters on the Static Strength and Dynamics for Spiral Bevel Gear
Authors: Feng Zhiheng , Song Chaosheng
Published: July 2017

Considering the geometry design parameters, a quasi-static mesh model of spiral bevel gears was established and the mesh characteristics were computed. Considering the time-varying effects of mesh points, mesh force, line-of-action vector, mesh stiffness, transmission error, friction force direction, and friction coefficient, a nonlinear lumped parameter dynamic model was developed for the spiral bevel gear pair. Based on the mesh model and the nonlinear dynamic model, the effects of main geometry parameters on the contact and bending strength were analyzed. Also, the effects on the dynamic mesh force and dynamic transmission error were investigated. Results show that higher value for the pressure angle, root fillet radius, and the ratio of tooth thickness tend to improve the contact and bending strength and to reduce the risk of tooth fracture. Improved gears have a better vibration performance in the targeted frequency range. Finally, bench tests for both types of spiral bevel gears were performed. Results show that the main failure mode is the tooth fracture and the life was increased a lot for the spiral bevel gears with improved geometry parameters compared to the original design.
Metric Projection Operator and Continuity of the Set-Valued Metric Generalized Inverse in Banach Spaces
Authors: Shang Shaoqiang , Zhang Jingxin
Published: July 2017

In this paper, continuous homogeneous selection and continuity for the set-valued metric generalized inverses T∂ in 3-strictly convex spaces are investigated by continuity of metric projection. The results are an answer to the problem posed by Nashed and Votruba. Moreover, authors prove that there exists a proximinal hyperplane H such that PH is continuous and H is not approximative compact.
Association between Serum Homocysteine Level and Obstructive Sleep Apnea: A Meta-Analysis
Authors: Li Kun , Zhang Jing , Qin Yanwen , Wei Yong-Xiang
Published: July 2017

Background. Obstructive sleep apnea (OSA) is a common problem that affects human health. Researches have reported a variety of results with reference to the association between OSA and serum homocysteine (Hcy) level. This meta-analysis is proposed to figure out the association between serum Hcy level and OSA.Methods. Eligible studies were identified via searching PubMed, Embase, and China National Knowledge Infrastructure (CNKI). Two independent reviewers reviewed studies. The Newcastle-Ottawa Quality Assessment Scale (NOS) was employed for quality assessment of included studies. RevMan (5.1) software and STATA (12.0) software were applied to data analyses.Results. 10 studies containing 839 subjects were included in the present meta-analysis; results revealed that Hcy levels in OSA group were 2.40 μmol/l higher than that in control group (95% confidence interval: 0.6 to 4.20,P<0.01;I2=96%). Subgroup analysis showed a significant increase of serum Hcy level in OSA patients compared with healthy controls when apnea hyperpnoea index (AHI) >= 30.Conclusions. Serum Hcy levels and OSA have close-knit and significant association. Analyses demonstrated that patients with OSA had a higher serum Hcy level than healthy controls. In addition, this difference is more significant in moderate or severe OSA patients.
Transit-Amplifying Cells in the Fast Lane from Stem Cells towards Differentiation
Authors: Rangel-Huerta Emma , Maldonado Ernesto
Published: August 2017

Stem cells have a high potential to impact regenerative medicine. However, stem cells in adult tissues often proliferate at very slow rates. During development, stem cells may change first to a pluripotent and highly proliferative state, known as transit-amplifying cells. Recent advances in the identification and isolation of these undifferentiated and fast-dividing cells could bring new alternatives for cell-based transplants. The skin epidermis has been the target of necessary research about transit-amplifying cells; this work has mainly been performed in mammalian cells, but further work is being pursued in other vertebrate models, such as zebrafish. In this review, we present some insights about the molecular repertoire regulating the transition from stem cells to transit-amplifying cells or playing a role in the transitioning to fully differentiated cells, including gene expression profiles, cell cycle regulation, and cellular asymmetrical events. We also discuss the potential use of this knowledge in effective progenitor cell-based transplants in the treatment of skin injuries and chronic disease.
Bone Marrow-Liver-Spleen Type of Large B-Cell Lymphoma Associated with Hemophagocytic Syndrome: A Rare Aggressive Extranodal Lymphoma
Authors: Lyapichev Kirill A. , Chapman Jennifer R. , Iakymenko Oleksii , Ikpatt Offiong F. , Teomete Uygar , Sanchez Sandra Patricia , Vega Francisco
Published: August 2017

Recently, an unusual subtype of large B-cell lymphoma (LBCL) with distinctive clinicopathologic features has been recognized; it is characterized by involvement of bone marrow with or without liver and/or spleen, but no lymph node or other extranodal sites, usually associated with fever, anemia, and hemophagocytic lymphohistiocytosis (HLH). Because of this distinctive clinical presentation, it has been designated “bone marrow-liver-spleen” (BLS) type of LBCL. To date there is only one series of 11 cases of BLS type of LBCL with detailed clinical, pathologic, and cytogenetic data. Herein, we describe a case of BLS type LBCL presenting with associated HLH in a 73-year-old female. The bone marrow core biopsy showed cytologically atypical large lymphoma cells present in a scattered interstitial distribution and hemophagocytosis and infrequent large lymphoma cells were seen in the bone marrow aspirate smears. Circulating lymphoma cells were not seen in the peripheral blood smears. The patient underwent treatment with chemotherapy (R-CHOP) but unfortunately passed away 2 months after initial presentation. BLS type of LBCL is a very rare and clinically aggressive lymphoma whose identification may be delayed by clinicians and hematopathologists due to its unusual clinical presentation and pathologic features.
Quality Evaluation of Human Bone Marrow Mesenchymal Stem Cells for Cartilage Repair
Authors: Shiraishi Katsunori , Kamei Naosuke , Takeuchi Shunsuke , Yanada Shinobu , Mera Hisashi , Wakitani Shigeyuki , Adachi Nobuo , Ochi Mitsuo
Published: August 2017

Quality evaluation of mesenchymal stem cells (MSCs) based on efficacy would be helpful for their clinical application. In this study, we aimed to find the factors of human bone marrow MSCs relating to cartilage repair. The expression profiles of humoral factors, messenger RNAs (mRNAs), and microRNAs (miRNAs) were analyzed in human bone marrow MSCs from five different donors. We investigated the correlations of these expression profiles with the capacity of the MSCs for proliferation, chondrogenic differentiation, and cartilage repair in vivo. The mRNA expression of MYBL1 was positively correlated with proliferation and cartilage differentiation. By contrast, the mRNA expression of RCAN2 and the protein expression of TIMP-1 and VEGF were negatively correlated with proliferation and cartilage differentiation. However, MSCs from all five donors had the capacity to promote cartilage repair in vivo regardless of their capacity for proliferation and cartilage differentiation. The mRNA expression of HLA-DRB1 was positively correlated with cartilage repair in vivo. Meanwhile, the mRNA expression of TMEM155 and expression of miR-486-3p, miR-148b, miR-93, and miR-320B were negatively correlated with cartilage repair. The expression analysis of these factors might help to predict the ability of bone marrow MSCs to promote cartilage repair.
The Circular Economy of E-Waste in the Netherlands: Optimizing Material Recycling and Energy Recovery
Authors: Golsteijn Laura , Valencia Martinez Elsa
Published: July 2017

In the Netherlands, waste electric and electronic equipment (e-waste) is an important point for discussion on the circular economy agenda. This paper shows the Dutch example of how “waste” can be turned into a resource, and the climate change benefits from appropriate collection and recycling. It describes the avoided emissions of CO2-equivalents due to e-waste recycling and appropriate removal and destruction of (H)CFCs contained in cooling and freezing appliances. Six different e-waste categories were included, and the results of 2016 were compared to previous years (2009–2015). In 2016, 110,000 tonnes of e-waste were collected. 80% of this was recycled to useful materials. Additionally, it resulted in 17% energy recovery. That year, the recycling of e-waste and the removal of (H)CFKs resulted in approximately 416,000 tonnes of avoided emissions of CO2-equivalents. Although the phasing out of cooling and freezing appliances with (H)CFKs led to a general decrease in the quantity of avoided CO2 emissions over time, removal of (H)CFKs still explained most of the avoided CO2 emissions. Material recycling appeared particularly beneficial for cooling and freezing appliances and small and large household appliances. The paper ends with reasons to further close the loop and ways forward to do so.
Vertebral Artery Caught in the Fracture Gap after Traumatic C2/3 Spondylolisthesis
Authors: Henkelmann Ralf , Josten Christoph , Glasmacher Stefan , Heyde Christoph-Eckhard , Spiegl Ulrich Josef Albert
Published: August 2017

Background Context. Patient with a C2 fracture and entrapment of the right vertebral artery in the fracture gap. Purpose. Presentation of a case with follow-up until end of treatment. Study Design. Case report. Methods. A 25-year-old woman was brought into our emergency room after falling while riding a horse. She complained of pain in the cervical spine. Clinical examinations showed local tenderness at the upper cervical spine and painful impairment of the mobility of the neck, with no signs of neurological impairment. Radiological diagnostics revealed a traumatic C2/3 spondylolisthesis. A computer tomography (CT) angiographic scan showed a dislocation of the right vertebral artery into the fracture gap without injury to the artery. Open reduction and osteosynthesis were considered of too high risk. Therefore, we conducted fracture treatment with closed reduction and halo fixation. After removal of the halo fixator, the patient was given a soft cervical collar and was advised to rest for additional 6 weeks before beginning gradual activity. Results. Conventional follow-up revealed osseous consolidation and a CT angiographic scan showed consistent blood flow to the artery. Conclusion. Halo fixation was a safe and effective therapy strategy in the case of vertebral artery entrapment after traumatic C2 spondylolisthesis.
Discovery of MicroRNAs in Cardamom (Elettaria cardamomum Maton) under Drought Stress
Authors: Anjali N. , Nadiya F. , Thomas Jinu , Sabu K. K.
Published: July 2017

MicroRNAs (miRNAs) are endogenous, 19–24‐nucleotide‐long, noncoding RNAs found in animals, plants, and some viruses. Drought is one of the major limiting factors that negatively affect productivity of plants. To date, nothing is known about the regulatory roles of miRNAs in response to drought stress in cardamom. Cardamom collected from the natural forest area in Therakkudi in the Idamalayar forest range was selected for the study. Total RNA was isolated from leaves and stems of control and drought treated cardamom plant, which was used for library construction. Ion torrent sequencing of the two small RNA libraries prepared from plants raised under well irrigated and drought stressed treatments, respectively, created 3,938,342 and 4,083,181 primary reads. A total of 150 conserved and 20 novel microRNAs were identified from both the control and the treated libraries. Discovery of 17 differentially expressed miRNAs under drought stress suggests that these might have been involved in various biological processes to improve plant tolerance to water stress. This study is the first report of drought responsive miRNAs and their targets in cardamom. The outcome of this research could provide insights into the miRNA based regulatory mechanisms in response to drought stress in monocot plants.
Abstract 1065: MMP sensitive liposomes followed by radiotherapy improves tumor control in head and neck cancer mice models
Authors: Brogaard Rikke Y. , Khoo Allison , Eliasen Rasmus , Melander Fredrik , Chadha Awalpreet , Aziz Kathryn , Krishnan Sunil , Andresen Thomas L.
Published: July 2017

Many cancers at advanced stages require a combination of chemotherapy and radiotherapy. A big challenge with this approach is accumulated toxicity because both of these treatment modalities are non-selective and inevitably damage non-target tissues. Nanoparticles such as liposomes provide the ability to differentiate between healthy and cancerous tissues and thus offer efficient delivery of chemotherapy to cancerous tissues. Recently, we developed a matrix metalloproteinase (MMP)-sensitive liposomal platform to carry anticancer agents to the tumor. High local expression of MMPs within the tumor microenvironment ensures bioavailability of the carried agent by converting a polyethylene glycol (PEG)ylated anionic liposome into a dePEGylated cationic liposome that is readily internalized by cells. Using oxaliplatin-loaded MMP-sensitive liposomes, we previously demonstrated great in-vivo efficacy in mice bearing CT26 tumors.

In the present study, we assessed the combinatorial effect of MMP-sensitive liposomes and radiotherapy in head and neck squamous cell carcinoma models. Using a clonogenic cell survival assay, we evaluated MMP-sensitive liposomes combined with radiotherapy. A slightly sensitizing effect was produced by oxaliplatin-loaded MMP-sensitive liposomes while free oxaliplatin produced an additive effect. Similarly, levels of platinum intercalated into DNA were three times higher in cells treated with oxaliplatin-loaded MMP-sensitive liposomes than in those treated with free oxaliplatin. The in-vivo efficacy of oxaliplatin-loaded MMP-sensitive liposomes combined with radiotherapy was studied in the same tumor models, FaDu and HN5, where zymogram gels confirmed an MMP-positive tumor microenvironment. MMP-sensitive liposomes and radiation had a much greater anti-tumor effect than any of the monotherapies or free oxaliplatin combined with radiation. In FaDu, the mean tumor size between liposomes + radiation and liposomes only were significantly different (p<0.05). Thus, our preliminary results suggest that MMP-sensitive liposomes in combination with radiation hold a great potential for clinical translation. The MMP-sensitive liposome offers a valuable tool to deliver the payload in a controlled fashion into the tumor microenvironment, where radiation can potentially amplify the therapeutic index.

Note: This abstract was not presented at the meeting.

Citation Format: Rikke Y. Brogaard, Allison Khoo, Rasmus Eliasen, Fredrik Melander, Awalpreet Chadha, Kathryn Aziz, Sunil Krishnan, Thomas L. Andresen. MMP sensitive liposomes followed by radiotherapy improves tumor control in head and neck cancer mice models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1065. doi:10.1158/1538-7445.AM2017-1065
Abstract 1149: Targeting Rad6B suppresses melanomagenesis
Authors: Sarma Ashapurna , Petit Sarah , Liu Fangchao , Nangia-Makker Pratima , Mao Guangzhao , Shekhar Malathy
Published: July 2017

Active β-catenin signaling in melanoma is associated with aggressive disease. We have previously shown that Rad6B, an ubiquitin conjugating enzyme, is a positive regulator of β-catenin stability and transcriptional activity, and is itself a transcriptional target of β-catenin. This stabilization is mediated by Rad6B-induced K63-linked polyubiquitination of β-catenin that renders it insensitive to 26S proteasomal degradation. Immunohistochemical analysis of human cutaneous melanoma samples showed the first detectable expression of Rad6B in melanocyte hyperplasia and continued Rad6B and β-catenin overexpression in primary and metastatic melanomas. These data implicate a critical role for Rad6B in melanocyte transformation and a continuing role in melanoma progression. To analyze the role of Rad6B in melanomagenesis, we targeted Rad6B expression/activity in human M14 metastatic melanoma cells by using a Rad6-selective small molecule inhibitor SMI#9 and the CrispR/Cas9 gene editing system. Immunoblot analysis showed that compared to controls, M14 cells treated with SMI#9 showed decreased levels of β-catenin, and β-catenin driven transcriptional targets Rad6, vimentin, Mitf-M, and Melan A. Although Snail levels were not altered, SMI#9 treated cells showed increase in phosphorylated Snail. Immunocytochemical staining verified the western blot data and showed cytoplasmic relocalization of PCNA and Snail in SMI#9 treated cells which is consistent with increase in phosphorylated Snail. Concordant with the decrease in vimentin and unphosphorylated Snail levels, Rad6B-inhibited cells display poor capacity to migrate as compared to controls. Whereas Rad6B knockout cells were severely growth impaired, Rad6B edited clones showing partial expression (potentially from only one allele) similarly showed decreased levels of β-catenin, vimentin, and Mitf-M. Similar to Rad6B-inhibited cells, Rad6B edited cells were migration- and invasion-impaired. Whereas control cells produced robust tumors and overt lung metastases, the Rad6B gene edited cells were poorly tumorigenic. Rad6B gene edited clones showed complete loss of Melan A. Since Mitf-M is a transcriptional regulator of Melan A and a key player in melanocyte lineage specification, our data suggest that targeting Rad6B could potentially inhibit melanomagenesis by reprogramming melanoma cells. Supported by NIH CA178117 and 3Balls Racing.

Citation Format: Ashapurna Sarma, Sarah Petit, Fangchao Liu, Pratima Nangia-Makker, Guangzhao Mao, Malathy Shekhar. Targeting Rad6B suppresses melanomagenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1149. doi:10.1158/1538-7445.AM2017-1149
Abstract 1407: Translational regulation of RPA2 via IRES by UNR and eIF3a
Authors: Cui Jia-Jia , Wang Lei-Yun , Yin Ji-Ye
Published: July 2017

Purpose:

Translation is a critical step in the process of genetic information expression. Internal ribosome entry site (IRES) element is a RNA sequence with a complex structure, which plays an important role in cap independent translation regulation. The activation of RPA2 IRES element can cause its abnormal expression and finally effects DNA repair pathway. We conducted series of assays to explore the mechanism of translation initiation regulation of RPA2 via IRES by UNR and eIF3a

Methods:

Biotin pull down assay was taken to investigate the physical interaction between RPA2 IRES and UNR. UNR was knocked down and overexpressed in H1299, A549 and SK-MES cell lines. Western blot and real-time PCR were used to detect protein level and mRNA level respectively. For interaction of eIF3a with UNR, CO-IP assay and co-localization assay were conducted. And GST pull down assay was carried out to further identify their exact binding domains. RPA2 IRES-interacting domains of UNR and eIF3a were explored with EMSA assay.

Results:

UNR protein could directly bind to RPA2 IRES as well as to eIF3a, and UNR regulated the protein expression of RPA2 in H1299, A549 and SK-MES cells, while the mRNA level of RPA2 remained no change. UNR interacted with the first domain of eIF3a and with RPA2 IRES via its own first domain. However, we have not found a clue for the direct interaction of eIF3a with RPA2 IRES yet.

Conclusion:

UNR cooperated with eIF3a to regulate the RPA2 IRES activity and hence to regulate the RPA2 protein expression. This might be a regulation mechanism of cellular internal ribosomal entry site affecting translation initiation, the rate-limiting step of translation.

Citation Format: Jia-Jia Cui, Lei-Yun Wang, Ji-Ye Yin. Translational regulation of RPA2 via IRES by UNR and eIF3a [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1407. doi:10.1158/1538-7445.AM2017-1407
Abstract 1702: Multimeric anti-DR5 IgM antibody displays potent cytotoxicity in vitro and promotes tumor regression in vivo
Authors: Wang Beatrice , Kothambalwala Tasnim , Hinton Paul , Ng Dean , Saini Avneesh , Baliga Ramesh , Keyt Bruce
Published: July 2017

Death receptor 5 (DR5) is a member of the TNF receptor superfamily that induces apoptosis upon receptor trimerization. It is expressed on many tumor types and has therefore been an important target for developing antibody based treatments of epithelial, solid tumors. However several agonistic Anti-DR5 IgG antibodies that have demonstrated efficacy in preclinical models have been unsuccessful in clinical trials, likely due to insufficient receptor crosslinking by bivalent IgGs. We have developed a multimeric anti-DR5 IgM antibody which has strong avidity for the receptor. The IgM binds Colo205 cells and triggers apoptosis, and is 1000-fold more potent than the respective IgG and 100-fold more potent than crosslinked IgG in vitro. Anti-DR5 IgM displays strong in vitro potency across a panel of tumor cell lines, including ones that are IgG-resistant. Anti-DR5 IgM causes tumor regression and delays tumor growth in various in vivo xenograft models including Colo205, HCT15 and MDA-MB231. These results support the development of an human anti-DR5 IgM therapeutic with the potential to treat solid tumors.

Citation Format: Beatrice Wang, Tasnim Kothambalwala, Paul Hinton, Dean Ng, Avneesh Saini, Ramesh Baliga, Bruce Keyt. Multimeric anti-DR5 IgM antibody displays potent cytotoxicity in vitro and promotes tumor regression in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1702. doi:10.1158/1538-7445.AM2017-1702
Abstract 193: Inhibitors of MPS1: Discovery of CCT289346, a highly potent, selective and orally available preclinical candidate
Authors: Woodward Hannah L. , Innocenti Paolo , Cheung Kwai-Ming J. , Naud Sébastien , Hayes Angela , Henley Alan T. , Faisal Amir , Mak Grace , Box Gary , Westwood Isaac M. , Carter Michael , Valenti Melanie , Brandon Alexis De Haven , O’Fee Lisa , Saville Harry , Burke Rosemary , Montfort Rob van , Raynaud Florence , Eccles Suzanne A. , Linardopoulos Spiros , Blagg Julian , Hoelder Swen
Published: July 2017

MPS1 (also known as TTK), is a dual-specificity protein kinase and one of the main components of the spindle assembly checkpoint. Cancer cells heavily rely on MPS1 to cope with aneuploidy resulting from aberrant numbers of chromosomes and MPS1 has been found to be upregulated in a large number of tumor types. Extensive work by us and other groups has shown that MPS1 inhibitors are effective against a variety of cancers, particularly when used in combination with other drugs, for example, tubulin-targeting agents. We recently reported the structure-based design and discovery of a series of pyrido[3,4-d]pyrimidines inhibitors of MPS1 (1). Advanced compounds showed very potent inhibition of MPS1 in biochemical and cellular assays. However, these compounds suffered from high lipophilicity and pronounced metabolism in human liver microsomes preventing progression into preclinical development. Here we report the optimisation of this series ultimately yielding CCT289346, our preclinical candidate. CCT289346 shows excellent potency, kinase selectivity, and ADME properties including stability in human liver microsomes. The compound has been produced on a kilogram scale and is currently undergoing preclinical development. We will discuss our design approach and hypotheses leading to the discovery of CCT289346 and disclose in vivo efficacy data. References 1. Innocenti P et al. Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach. Journal of Medicinal Chemistry. 2016; 59(8):3671-88.

Citation Format: Hannah L. Woodward, Paolo Innocenti, Kwai-Ming J. Cheung, Sébastien Naud, Angela Hayes, Alan T. Henley, Amir Faisal, Grace Mak, Gary Box, Isaac M. Westwood, Michael Carter, Melanie Valenti, Alexis De Haven Brandon, Lisa O’Fee, Harry Saville, Rosemary Burke, Rob van Montfort, Florence Raynaud, Suzanne A. Eccles, Spiros Linardopoulos, Julian Blagg, Swen Hoelder. Inhibitors of MPS1: Discovery of CCT289346, a highly potent, selective and orally available preclinical candidate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 193. doi:10.1158/1538-7445.AM2017-193
Abstract 2183: Targeted delivery of hyaluronic acid-labeled chitosan nanoparticles against CD44 overexpressed endothelial cell for tumor angiogenesis therapy
Authors: Kim Gahee , Han Heedong
Published: July 2017

Objective: RNA interference (RNAi)-based approaches hold great potential for cancer therapy. Here, we developed siRNA-incorporated chitosan nanoparticles coated with hyaluronic acid (HA-CH-NP/siRNA) to target CD44 receptor on the surface of tumor endothelial cells

Methods: Size and zeta potential of HA-CH-NP were measured by light scattering with a particle size analyzer and Zeta Plus. Morphology of HA-CH-NP was observed by atomic force microscopy (AFM). HA-based selective binding of HA-CH-NP on the CD44 positive cells was assessed by flow cytometry and immunohistochemistry (IHC) analysis. Therapeutic efficacy was examined in orthotopic mouse models of ovarian carcinoma. PLXDC1 mRNA was quantified using real-time reverse transcription-polymerase chain reaction (RT-PCR). Additionally, biological effect on angiogenesis (MCD), cell proliferation (Ki67), and apoptosis (TUNEL) in the tumor tissue were examined by IHC analysis.

Results: HA-CH-NP/siRNA was 185 ± 10 nm in size and zeta potential was 26.4 mV, respectively. The loading efficiency of siRNA into HA-CH-NP/siRNA was up to 60%. We confirmed selective binding efficiency of HA-CH-NP/siRNA with CD44+ tumor endothelial cells was increased 2.1-fold compared to CH-NP/siRNA. PLXDC1 silencing using HA-CH-NP/siRNA significantly inhibited tumor growth in A2780 tumor growth in A2780 tumor-bearing mice compared to control (p < 0.0001), and mRNA expression of PLXDC1 was significantly decreased in HA-CH-NP/siRNA treated group. In addition, treatment with HA-CH-NP/siRNA resulted in significant inhibition of cell proliferation (p < 0.05), microvessel density ( p < 0.05), and increased cell apoptosis (p < 0.05).

Conclusion: This study demonstrated that HA-CH-NP/siRNA was a novel and highly selective delivery system for siRNA with potential for broad applications for tumor angiogenesis therapy.

Citation Format: Gahee Kim, Heedong Han. Targeted delivery of hyaluronic acid-labeled chitosan nanoparticles against CD44 overexpressed endothelial cell for tumor angiogenesis therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2183. doi:10.1158/1538-7445.AM2017-2183
Abstract 2186: Peptide-cleavable maytansinoid (ADCs) induce high bystander killing leading to improved anti-tumor activity in vivo
Authors: Widdison Wayne C. , Costoplus Juliet A. , Ponte Jose F. , Lanieri Leanne , Setiady Yulius , Dong Ling , Skaletskaya Anna , Wu Rui , Qiu Qifeng , Kovtun Yelena , Chari Ravi V.
Published: July 2017

Antibodies targeting surface antigens on cancer cells typically have progressively lower access to tumor cells that are further removed from blood vessels. Also, the antibody will not bind to cells in the tumor mass that do not express antigen, including stromal cells of the tumor, many of which reportedly aid in the survival or metastasis of cancer cells.

ADCs can bind to antigen positive cancer cells, after which they are internalized and catabolized to release one or more cytotoxic metabolite(s) that can kill the targeted cell. Metabolites that are membrane permeable may also diffuse into and kill neighboring cells, often called bystander cells, that would normally be less accessible.

The goal of this work was to design ADCs that would have increased bystander activity, which could result in greater killing of cancer cells and stromal cells in the tumor environment. We have prepared a new type of peptide-cleavable immolative ADC (PCI-ADC) that efficiently releases membrane permeable cytotoxic maytansinoid metabolites upon cleavage of the peptide linker, followed by immolation. Several PCI-ADCs were prepared that release metabolites having different degrees of hydrophobicity. As the hydrophobicity of the metabolite increased, the PCI-ADCs’ bystander activity also increased. The lead PCI-ADC generally displayed a similar degree of in vitro cytotoxicity as maytansinoid ADCs that utilize disulfide linkers, however the PCI-ADC induced significantly more bystander killing. In mice bearing large tumor xenografts (250 mm3) or tumor xenografts that express the target antigen heterogeneously, PCI-ADCs were found to be more efficacious than maytansinoid ADCs that use disulfide linkers, as well as our recently reported peptide-para-anilino maytansinoid ADCs. The nature of the amino acid residues in the peptide linker of the PCI-ADC was also altered so that the tolerability of the ADCs in mice could be increased without impeding efficacy.

In conclusion, we have developed a promising new type of maytansinoid ADC, one that provides a high degree of bystander killing, improved activity in homogeneous and heterogeneous tumor models in vivo, and has a different mechanism of metabolite release than current maytansinoid based ADCs.

Citation Format: Wayne C. Widdison, Juliet A. Costoplus, Jose F. Ponte, Leanne Lanieri, Yulius Setiady, Ling Dong, Anna Skaletskaya, Rui Wu, Qifeng Qiu, Yelena Kovtun, Ravi V. Chari. Peptide-cleavable maytansinoid (ADCs) induce high bystander killing leading to improved anti-tumor activity in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2186. doi:10.1158/1538-7445.AM2017-2186
Abstract 2241: Diosmetin induces apoptosis in human prostate carcinoma cells via the Rictor pathway invitro and inhibits tumor growth in vivo
Authors: Patel Riddhi , Pakradooni Rebecca , Khalifa Ahmad , Bhaskaran Natarajan , Shukla Sanjeev
Published: July 2017

Cell growth is a fundamental biological process, where mTOR (mammalian target of rapamycin) pathway has its role, regulates cell growth by coordinating energy and nutrient signals with growth factor. mTOR protein kinase have two different complexes; complex-I contains major component raptor; a target of rapamycin and complex II; insensitive to rapamycin, has major component rictor. Rictor is important as it phosphorylates Ser-473 of Akt/PKB, which is essential for full Akt/PKB activation. Reports suggested that overexpression of mTOR in prostate cancer tissues, which may have potential role in prostate cancer progression. The known mTOR inhibitor rapamycin is not specific for mTOR-II complex, as it doesn’t inhibit main component Rictor. We need to have effective chemo-preventive agents, which can modulate Rictor signaling cascade to inhibit prostate cancer. Diosmetin (5, 7-Trihydroxy-4′-methoxyflavone), a natural flavonoid present in citrus plant, has anti-mutagenic and anti-allergic properties. Earlier we demonstrated growth factors Insulin-like growth factor-1 and cytokine (IL-6) induces Rictor expression, and phosphorylated Akt at Ser-473. Using diosmetin in concentration dependent fashion (5-40µM) to LNCaP and PC-3 cells down regulated phosphorylation of Rictor (Thr1135), Akt (Ser-473) and PKCα (Ser-657) expressions. This resulted in downregulation of survival molecules; Survivin and X-linked inhibitor of apoptosis protein, which induced apoptosis and inhibited cells growth. Luciferase tag PC-3 cells orthotopic implant in ventral prostate of nude mice represented significant decrease in tumor volume of diosmetin (20 and 50µg/animal/day) fed mice compared to control mice. Similarly bioluminescence imaging of orthotopically implanted mice represented decreased tumor luciferase activity after diosmetin feeding than control mice. Moreover, diosmetin feeding to tumor bearing nude mice reduced the phosphorylation of Rictor, (Thr1135), Akt (Ser-473) and PKCα (Ser-657) expressions and induced apoptotic events to inhibit tumor growth significantly. Based on results we may suggest diosmetin can be developed as an anticancer agent for prostate cancer.

Citation Format: Riddhi Patel, Rebecca Pakradooni, Ahmad Khalifa, Natarajan Bhaskaran, Sanjeev Shukla. Diosmetin induces apoptosis in human prostate carcinoma cells via the Rictor pathway invitro and inhibits tumor growth in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2241. doi:10.1158/1538-7445.AM2017-2241
Abstract 2515: Understanding metabolic dysfunction in retinoblastoma development
Authors: Guha Nilanjan , Livi Carolina , Babu Vishnu Suresh , Winer Lisa , SA Deepak , Lateef Syed , Gundimeda Seetaraman , Padmanabhan Arunkumar , Dranka Brian , Ghosh Arkasubhra
Published: July 2017

Metabolic dysfunction or reprogramming is the underlying cause of many diseases including cancer. In this study, we looked into the transcriptomic and metabolomic profile of retinoblastoma (Rb), a pediatric eye cancer, from tumor and normal tissue, aqueous humor, vitreous humor and tear. The samples were collected from enucleated eyes of 9 subjects and 2 deceased controls, whose cause of death is not due to any eye related disease. The study was corroborated with cell line models of retinoblastoma, used for metabolic phenotyping. Combined pathway analysis of transcriptomics data from subject tissue samples and retinoblastoma cell line WERI-Rb-1 revealed a significant overlap in the differentially regulated genes belonging to both glycolysis and OXPHOS pathways. The results were correlated with Rb1 overexpressed and its respective control also. To better understand the implications of these two major pathways in the progression of retinoblastoma, metabolic study using Seahorse analyzer enables measurement of extracellular flux (oxygen consumption rate and extracellular acidification rate) to provide insight into mitochondrial function and glycolytic activity. Using a pharmacological approach, the contribution of glucose, glutamine and fatty acid oxidation pathways can be assessed. Overall the study demonstrates the value of using a multi-omics approach with functional metabolic profiling to understand the extent of metabolic dysfunction in retinoblastoma and also to identify implications of various biological pathways in Rb.

Citation Format: Nilanjan Guha, Carolina Livi, Vishnu Suresh Babu, Lisa Winer, Deepak SA, Syed Lateef, Seetaraman Gundimeda, Arunkumar Padmanabhan, Brian Dranka, Arkasubhra Ghosh. Understanding metabolic dysfunction in retinoblastoma development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2515. doi:10.1158/1538-7445.AM2017-2515
Abstract 2563: LSD1 maintains differentiation and survival of mammary luminal cells and suppresses invasion of luminal breast cancer cells via GATA3
Authors: Hu Xin , Xiang Dongxi , Tao Luwei , Xie Ying , Jin Yue , Guo Yidi , Pinello Luca , Yuan Guo-Cheng , Li Zhe
Published: July 2017

LSD1 (also known as KDM1A) is a histone demethylase that has been shown to play both oncogenic and tumor suppressor roles in breast cancer. However, the exact context under which it functions as a tumor suppressor or oncoprotein remains largely elusive. To address this, we characterized its role in normal mammary epithelial cells (MECs) and found MEC-specific ablation of Lsd1 largely phenocopied that of Gata3, which encodes a master regulatory transcription factor for luminal MECs. In the luminal lineage, LSD1-loss led to reduction in both mature ductal and alveolar luminal subpopulations. In human luminal breast cancer cells, we found LSD1 interacts with GATA3 and their common target genes are highly related to breast cancer. In particular, we found LSD1 might be recruited by GATA3 to the GATA3 promoter region, to positively regulate GATA3 expression via demethylation of H3K9me2. Knockdown of LSD1 led to increased invasion of luminal breast cancer cells, in part via downregulation of GATA3 and multiple cell junction genes (e.g., CDH1, VCL, CTNNA1), as well as upregulation of mammary stem/progenitor cell genes (e.g., ELF5, ITGB1). However, LSD1 knockdown also led to reduced proliferation of luminal breast cancer cells, in part via downregulation of RBBP4 (encoding a Histone-binding protein) and upregulation of CDKN1A (encoding p21). Collectively, our data suggest that LSD1 is required for maintaining luminal MEC differentiation and survival and for suppressing luminal breast cancer cell invasion, in part via GATA3. As inhibitors of LSD1 are currently under clinical trials (e.g., in leukemia), our data suggest that although treatment of luminal breast cancer by the LSD1 inhibitor may lead to reduced tumor cell proliferation (and thus tumor shrinkage), the treatment may also lead to increased invasion of surviving breast cancer cells. Thus, our study is expected to have important implications for developing better epigenetic therapy in an individualized, context-dependent fashion.

Citation Format: Xin Hu, Dongxi Xiang, Luwei Tao, Ying Xie, Yue Jin, Yidi Guo, Luca Pinello, Guo-Cheng Yuan, Zhe Li. LSD1 maintains differentiation and survival of mammary luminal cells and suppresses invasion of luminal breast cancer cells via GATA3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2563. doi:10.1158/1538-7445.AM2017-2563
Abstract 2584: The UCSC Xena system for cancer genomics data visualization and interpretation
Authors: Goldman Mary , Craft Brian , Zhu Jingchun , Haussler David
Published: July 2017

The UCSC Xena platform (http://xena.ucsc.edu/) allows biologists and bioinformaticians to securely analyze and visualize their private functional genomics data in the context of public genomic and clinical data sets. The Xena platform consists of a set of federated data hubs and the Xena browser, which integrates across hubs, providing one location to analyze and visualize all data. Our expanding public Xena Data Hubs currently hosts 1400+ data sets from more than 35 cancer types, as well as Pan-Cancer data sets. Our public data hubs serve seminal cancer genomics and functional genomics data set to the scientific community, including the latest TCGA, TARGET, ICGC, and GTEx data sets. We support most data types including somatic and germline SNPs, INDELs, large structural variants, CNV, gene-, transcript-, exon- protein-, miRNA-expression, DNA methylation, phenotypes, clinical data, subtype classifications and genomic biomarkers. Additionally, investigators’ own functional genomics data can be hosted on private hubs running on their laptop or behind the firewall. Data is integrated on the UCSC Xena Browser, allowing biologists to view and interpretation of their genomic data in the context of a large collection of cancer genomics data sets such as TCGA. The lightweight Xena data hubs are straightforward to install on Windows, Mac and Linux operating systems and loading data is easy using either our application or command line interface. This system of the browser and hubs helps researchers combine new or preliminary results from their laptops or internal servers, or even data from a new paper, securely with vetted data from the public sphere.

Visualizations and analyses include dynamic Kaplan-Meier survival analysis to assess survival stratification by any information in addition to our visual spreadsheet, scatter plots and bar graphs. We seek feedback at our poster on new visualizations and functionalities.

Citation Format: Mary Goldman, Brian Craft, Jingchun Zhu, David Haussler. The UCSC Xena system for cancer genomics data visualization and interpretation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2584. doi:10.1158/1538-7445.AM2017-2584
Abstract 2628: BGB-A425: a humanized anti-human Tim-3 antibody that exhibits strong immune cell activation
Authors: Zhang Tong , Xue Liu , Zhang Jing , Liu Qi , Ma Jie , Zhang Yi , Shi Yingdi , Hou Hongjia , Peng Hao , Liu Ning , Zhang Yilu , Song Xiaomin , Li Yucheng , Song Jing , Wang Lai , Wei Min , Li Kang
Published: July 2017

Background: Tim-3 (T-cell immunoglobin and mucin-domian containing-3) is a “checkpoint” inhibitory receptor, which is primarily expressed in activated or “exhausted” T cells, NK cells, macrophages and DCs. Engagement of Tim-3 receptor by its ligand phosphatidylserine (PtdSer) or galectin-9 leads to activation of negative regulatory signaling in T-cells, promoting functional exhaustion of tumor-infiltrating T-lymphocytes. BGB-A425 is a novel humanized IgG1 (variant) anti-Tim-3 antibody under preclinical development. The immunomodulatory activity of BGB-A425 was evaluated both in vitro and in vivo.

Materials and methods: BGB-A425 was generated through hybridoma fusion, humanized by CDR grafting and structural simulation. The Fc region (IgG1) of BGB-A425 was engineered to remove Fc gamma receptor (FcγR) binding. The binding affinity and specificity were studied by ELISA, FACS and SPR (Biacore). The immunomodulatory functions of BGB-A425 were evaluated using primary immune cells as well as cell lines.

Results: BGB-A425 binds to the extracellular domain of human Tim-3 with high affinity (KD = 0.36 nM) and specificity. In a competition assay, BGB-A425 efficiently blocks the interactions between Tim-3 and PtdSer. In vitro, BGB-A425 significantly enhances IFN-γ production of primary T cells and NK-mediated cytotoxicity against tumor cells. In a MLR assay, BGB-A425 augments T-cell response to allogeneic antigens either alone or in combination with an anti-PD-1 antibody BGB-A317. Besides blocking Tim-3, BGB-A425 can also induce the internalization of Tim-3 receptor on cell surface. In vivo, BGB-A425 in combination with BGB-A317 inhibits tumor growth in a mouse xenograft cancer model.

Conclusions: BGB-A425 demonstrates potent activity to stimulate immune cell function both in vitro and in vivo, supporting its clinical development for the treatment of human cancers.

Citation Format: Tong Zhang, Liu Xue, Jing Zhang, Qi Liu, Jie Ma, Yi Zhang, Yingdi Shi, Hongjia Hou, Hao Peng, Ning Liu, Yilu Zhang, Xiaomin Song, Yucheng Li, Jing Song, Lai Wang, Min Wei, Kang Li. BGB-A425: a humanized anti-human Tim-3 antibody that exhibits strong immune cell activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2628. doi:10.1158/1538-7445.AM2017-2628
Abstract 3083: Prior irradiation results in elevated programmed death 1 (PD-1) in T cells
Authors: Chen Renxiang , Li Deguan , Fornace Albert J. , Li Henghong
Published: July 2017

It is well known that radiation has long-lasting effects on the immune system. In this study we address the question whether these radiation-induced adverse effects on T cell activation are associated with alterations of T cell inhibitory receptors. Expression levels of inhibitory receptors on T cells were analyzed at multiple post-radiation time points ranging from one to four weeks in mice receiving whole body irradiation. The level of the checkpoint receptor, PD-1, on different T cell subpopulations was determined. Our results showed that prior irradiation resulted in significant elevated expression of PD-1 in both CD4+ and CD8+ populations. T cells with elevated PD-1 mostly were either central memory or naïve cells. In addition, the feedback induction of PD-1 expression in activated T cells declined with time after radiation. Taken together, the elevated PD-1 level observed at weeks after radiation exposure is connected to T cell dysfunction. Similar changes were seen in samples from tumor patients receiving radiotherapy. Recent preclinical and clinical studies have shown that radiation alters the immune-modulatory microenvironment in tumor tissue, and implies that a combination of radiotherapy and T cell checkpoint blockade immunotherapy including targeting the PD-L1/PD-1 axis may potentiate the antitumor response. Therefore, understanding the dynamic changes in PD-1 levels in T cells after radiation should help in the development of a more effective therapeutic strategy.

Citation Format: Renxiang Chen, Deguan Li, Albert J. Fornace, Henghong Li. Prior irradiation results in elevated programmed death 1 (PD-1) in T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3083. doi:10.1158/1538-7445.AM2017-3083