tbuckley/cabot-search huggingface dataset:
Abstract LB-069: <i>In vivo</i> delivery of asymmetric gene-silencing RNAs targeting CTNNB1 and PD-L1 show a broad spectrum of potent antitumor activities in preclinical cancer models
Authors: Youzhi Li, Yuan Gao, Yuxin Wang, Jie Su, Eric Hsu, Ewa Wybieralska, Janet Huang, Keyur Gada, Jun Oishi, Xiaoshu Dai, Erina Koga, Wei Li, Xiangao Sun, Emily Brooks, Chiang J. Li
Journal: Cancer Research (2017)

Abstract RNAi (RNA interference) technology has the potential to target any genes causing disease, including conventionally “undruggable” targets in cancer. We previously discovered aiRNA (asymmetric interfering RNA), a next generation of gene-silencing technology with improved gene silencing efficiency and reduced off-target effects in comparison with siRNA. We have recently developed a nanoscale formulation that encapsulates therapeutic aiRNAs targeting CTNNB1 and PD-L1, named BBI-801. Here we investigate the in vivo delivery and antitumor activity of BBI-801 encapsulating aiRNAs targeting CTNNB1 and PD-L1. CTNNB1 encodes undruggable β-catenin which is a cancer stemness gene that is broadly implicated in multiple cancer types PD-L1 gene encodes a key immune checkpoint factor that mediates cancer immune evasion. In our in vivo studies, we have achieved prolong silencing of β-Catenin/PD-L1 mRNA and protein in a dose-dependent manner in a wide variety of murine tumor models, including subcutaneous human tumor xenografts, orthotopic human liver and lung tumors, as well as syngeneic mouse colorectal, breast and lung tumors. Our biodistribution analysis of fluorescence-labeled aiRNA demonstrated that the delivery of BBI-801 to xenograft tumors happens within 5 minutes of aiRNA administration and lasts at least 8 hours. In all the models we examined, significant tumor growth inhibition by BBI-801 was achieved not only in β-Catenin over-expressed colorectal tumor models, SW480 and APCmin, but also in the rest of β-Catenin normal-expressed tumor models. Finally, BBI-801 is well tolerated and no signs of toxicity were observed after repeated dosing. These exciting data support further investigation of the anti-tumor potential of BBI-801 as an anticancer therapeutic in variety of tumor indications. Citation Format: Youzhi Li, Yuan Gao, Yuxin Wang, Jie Su, Eric Hsu, Ewa Wybieralska, Janet Huang, Keyur Gada, Jun Oishi, Xiaoshu Dai, Erina Koga, Wei Li, Xiangao Sun, Emily Brooks, Chiang J. Li. In vivo delivery of asymmetric gene-silencing RNAs targeting CTNNB1 and PD-L1 show a broad spectrum of potent antitumor activities in preclinical cancer 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 LB-069. doi:10.1158/1538-7445.AM2017-LB-069
Quo vadis: what is the future of periodontics? How will we get there?
Authors: Kenneth S. Kornman, William V. Giannobile, Gordon W. Duff
Journal: Periodontology 2000 (2017)

Abstract Approximately 40 years ago periodontists began systematically developing the evidence to treat predictably and prevent gingivitis and periodontitis. More recently, periodontists have been among a small group of skilled dental‐implant surgeons leading that revolution in dentistry. Today, much of the mild/localized moderate periodontitis is not treated by periodontists, and an increasing number of implants are placed by dentists with limited surgical training. The current field of periodontics includes a broad range of surgical skills and technologies to regenerate predictably destroyed tissues and manage complex interdisciplinary treatment that may, in some way, involve the tissues that support teeth and implants. In addition, periodontal researchers have shown that moderate‐to‐severe periodontitis increases the systemic inflammatory burden and transient bacteremias that result in a significant independent role for periodontitis in multiple systemic diseases. Although many periodontists have very advanced practices that incorporate certain aspects of the current and near‐future dimensions of periodontics, the innovations and technologies have not yet fully integrated throughout the specialty. It is an appropriate time to ask the question: Quo vadis? Which paths have the potential to deliver great value to our patients and to the health‐care system? And who will be our patients in the near future? We propose some key capabilities, knowledge and clinical applications. Perhaps most importantly, we propose new partnerships. Much of the vision centers around the application of special diagnostic technologies and surgical skills to help our dental colleagues better manage complex dental and periodontal cases and to deliver on the promise of reducing systemic inflammation sufficiently to enhance medical management of certain chronic diseases and reduce preterm births. The specialty has always been about retaining teeth in good health and in recent years has focused on controlling oral inflammation to enhance systemic health. We already have several of the key principles, concepts and technologies that are likely to define the role of periodontics in the evolving health‐care delivery system. Perhaps it is time to define the mission and start moving toward the future periodontics.
Abstract 2361: Pim kinase inhibition alters mRNA splicing in AML cell lines
Authors: Tejashree A. Joglekar, Xiang Li, Charles J. Bieberich
Journal: Cancer Research (2017)

Abstract Oncogenic kinase activity is a common feature of nearly all cancers and kinases are major targets for therapeutic intervention. Pim kinases are deregulated in hematopoietic cancers including Acute Myeloid Leukemia (AML), as well as prostate cancer. While cancer cells can become dependent on Pim activity to sustain proliferation, in normal adult tissues, Pim kinase activity appears to be dispensable. These features make Pim kinases an attractive target for cancer therapy, however, their physiological roles have not been fully characterized. Using the reverse in-gel kinase assay (RIKA), we identified a battery of novel Pim substrates that are involved in mRNA splicing regulation. We hypothesized that Pim family kinases regulate mRNA splicing through phosphorylation of splicing factors. Microarray analysis revealed more than 10,000 splicing changes in AML cells treated with the highly selective small molecule Pim kinase inhibitor AZD1208. Using RT-PCR analysis, multiple AZD1208-induced splicing changes were validated. To discern the mechanisms whereby Pim kinases regulate splicing, we determined whether Pim inhibition alters phosphorylation of serine/arginine-rich (SR) proteins. Inhibition of serine arginine protein kinase (SRPK) activity using a small molecular inhibitor (SRPIN340) reduced SR protein phosphorylation, whereas Pim kinase inhibition did not, suggesting that Pim kinases regulate splicing through an SRPK independent pathway. Comparison of splicing changes in AZD1208 and SRPIN340 treated AML cells demonstrated distinct patterns, providing further evidence of SRPK-independent splicing regulation by Pim kinases. Biomarkers of kinase inhibitor efficacy are critical components of clinical trials. These data suggest that changes in mRNA splicing may serve as a biomarker for assessing patient responsiveness to Pim inhibition therapy. Citation Format: Tejashree A. Joglekar, Xiang Li, Charles J. Bieberich. Pim kinase inhibition alters mRNA splicing in AML cell lines [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 2361. doi:10.1158/1538-7445.AM2017-2361
Abstract 3533: Connections between NF-κB misregulation and carcinogenesis
Authors: Donian I. Chyong, Aurian Naderi, Chase Lee, Ty Arpornsuksant, Allison Lu, Megha Dilip, Margaret Zhang, Young-Joon Surh, Eun-Ji Lee, Hye-Kyung Na
Journal: Cancer Research (2017)

Abstract In this review poster, we researched the function, regulation, and structure of NF-κB as it relates to carcinogenesis. Found in almost all animal cells, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a transcription factor that plays various roles in cellular proliferation, cell survival, inflammation, and T cell activation. There are two different NF-κB signaling pathways: the canonical pathway and the non-canonical pathway. NF-κB forms a p50/Rel A heterodimer in the canonical pathway and a p52/ Rel B heterodimer in the non-canonical pathway. NF-κB protein is normally sequestered in the cytoplasm as an inactive complex with a κB inhibitor (IκB) protein. Outside stimuli such as reactive oxygen species (ROS) and tumor necrosis factor alpha (TNF-α) activate cell surface receptors such as Toll-Like Receptors (TLRs) and Receptor Activators of NF-κB (RANK). These surface receptors, in turn, activate IκB kinase (IKK). IKK phosphorylates IκB, which causes ubiquitination of IκB, signaling proteasomes to degrade it. NF-κB then enters the nucleus through a nuclear pore and forms a transcription complex with coactivators and RNA polymerase. NF-κB binds to specific DNA-binding sites to induce transcription. One of the target genes of NF-κB encodes IκBs, so NF-κB regulates its own activity through a negative feedback loop. Because the cell maintains storage of the signaling protein NF-κB in the cytoplasm, NF-κB allows the cell to respond to sudden stimuli by activating quick changes in gene expression. Because proteins that promote cellular proliferation and cell survival are mainly transcribed through NF-κB activation, uncontrolled overactivation of this transcription factor has major implications in carcinogenesis. Many types of cancer cells have high levels of constitutively active NF-κB. Mutations in the genes for NF-κB itself or its inhibitors such as IκBs often found in cancer cells can cause cells to accelerate their proliferation or confer resistance to apoptosis. Some types of cancer cells secrete signaling molecules, inducing improper NF-κB activity. Because of the tumor promoting characteristics of NF-κB activation, a focus of current research is to find methods of suppressing NF-κB to kill cancer cells or slow their growth. We designed a 3D-printed model of the p50/RelA NF-κB protein using Jmol to highlight the relationship between its structure and function. Citation Format: Donian I. Chyong, Aurian Naderi, Chase Lee, Ty Arpornsuksant, Allison Lu, Megha Dilip, Margaret Zhang, Young-Joon Surh, Eun-Ji Lee, Hye-Kyung Na. Connections between NF-κB misregulation and carcinogenesis [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 3533. doi:10.1158/1538-7445.AM2017-3533
Distribution of Acid and Alkaline Phosphatase in Tumors, Normal Tissues, and the Tissues of Tumor-Bearing Rats and Mice
Authors: Jesse P. Greenstein
Journal: JNCI Journal of the National Cancer Institute (1942)

Distribution of Acid and Alkaline Phosphatase in Tumors, Normal Tissues, and the Tissues of Tumor-Bearing Rats and Mice Get access Jesse P. Greenstein Jesse P. Greenstein research fellow National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 2, Issue 5, April 1942, Pages 511–524, https://doi.org/10.1093/jnci/2.5.511 Published: 01 April 1942
Clinical similarity of the biosimilar ABP 501 compared with adalimumab after single transition: long-term results from a randomized controlled, double-blind, 52-week, phase III trial in patients with moderate-to-severe plaque psoriasis
Authors: K. Papp, H. Bachelez, A. Costanzo, P. Foley, M. Gooderham, P. Kaur, S. Philipp, L. Spelman, N. Zhang, B. Strober
Journal: British Journal of Dermatology (2017)

Background ABP 501, a U.S.A. Food and Drug Administration‐ and European Medicines Agency‐approved biosimilar, is highly similar to adalimumab in structure, function and pharmacokinetics. Objectives To demonstrate similarity in efficacy, safety and immunogenicity of ABP 501 vs. adalimumab for moderate‐to‐severe plaque psoriasis (clinical trial: NCT01970488). Methods Patients were randomized (1 : 1) to receive ABP 501 or adalimumab 40 mg every 2 weeks for 16 weeks. At week 16, patients with ≥ 50% improvement from baseline in Psoriasis Area and Severity Index (PASI) score were eligible to continue to week 52. Patients receiving ABP 501 continued; adalimumab patients were rerandomized (1 : 1) to continue adalimumab or undergo a single transition to ABP 501. Key efficacy assessments included percentage PASI improvement from baseline, PASI responders and mean change in affected body surface area from baseline to weeks 16, 32 and 50. Safety was monitored via adverse events (AEs) and antidrug antibodies (ADAs) were assessed. Results A total of 308 patients were rerandomized at week 16 (ABP 501/ABP 501, n = 152; adalimumab/adalimumab, n = 79; adalimumab/ABP 501, n = 77). PASI percentage improvements from baseline were similar across groups for weeks 16, 32 and 50 (range: 85·8–88·2%), with no significant differences detected across groups in percentages of PASI 50, 75, 90 and 100 responders. Changes from baseline in percentage body surface area affected were similar across groups and time points. No new safety signals were detected. AEs were balanced between groups. Percentages of patients with binding and neutralizing ADAs were similar across treatments. Conclusions ABP 501 and adalimumab have similar clinical efficacy, safety and immunogenicity profiles over 52 weeks, including after single transition, in this patient population.
Abstract 3146: Targeting ANXA3 in combination with sorafenib for the treatment of hepatocellular carcinoma
Authors: Man Tong, Steve Luk, Noelia Che, Jin Ding, Terence KW Lee, Stephanie Ma
Journal: Cancer Research (2017)

Abstract Sorafenib is the only FDA-approved tyrosine kinase inhibitor for targeted therapy in advanced HCC. Nevertheless, its efficacy is limited with only a modest improvement in patient outcome, likely due to acquired resistance. In-depth understanding of the molecular mechanism of sorafenib resistance is warranted for the development of novel treatment strategies. Recent studies by us and others have characterized liver tumor-initiating cells (T-ICs) to be a possible source of resistant and recurrent tumors and a plausible target for HCC treatment. Our group has previously identified CD133 to be a functional marker of liver T-ICs and found annexin a3 (ANXA3) to regulate cancer and stem cell-like properties in this subset of cells. Interestingly, our recent observations also found CD133+ liver T-ICs to be more resistant to sorafenib. Sorafenib resistant clones, established in HepG2 and Huh7 cells by continuous exposure to increasing concentrations of sorafenib, displayed enhanced abilities to migrate, invade, self-renew, and initiate tumor formation in immunodeficient mice, as well as higher expression of stemness associated genes. These two sorafenib resistant cell lines and two other sorafenib resistant HCC patient-derived xenografts established in a similar manner were also found to be enriched for CD133 and ANXA3 expression. Sorafenib resistant clones with ANXA3 stably suppressed were re-sensitized to sorafenib treatment and had diminished ability to migrate, invade, self-renew and initiate tumor growth in vivo, further substantiating the role of ANXA3 in mediating sorafenib resistance in HCC. Mechanistically, an activated PKC/ERK/FRA2 signaling axis was found to be responsible for driving this phenomenon. Clinically, ANXA3 expression was also found to have prognostic value as a higher ANXA3 expression in HCC patients who have received sorafenib treatment was correlated with poor overall survival. The combinatorial use of a homemade ANXA3 neutralizing antibody and sorafenib on HCC patient derived xenografts is now being investigated as a potential new treatment regimen for combating sorafenib resistance in HCC. Citation Format: Man Tong, Steve Luk, Noelia Che, Jin Ding, Terence KW Lee, Stephanie Ma. Targeting ANXA3 in combination with sorafenib for the treatment of hepatocellular carcinoma [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 3146. doi:10.1158/1538-7445.AM2017-3146
Abstract 2329: TMEM33 induces apoptosis via UPR signaling and autophagy in breast cancer cells
Authors: Rong Hu, Xiyuan Zhang, Leena Hilakivi-Clarke, Usha Kasid, Robert Clarke
Journal: Cancer Research (2017)

Abstract TMEM33 is a novel transmembrane protein that resides in the endoplasmic reticulum (EnR). It has been shown to activate the PERK and IRE1α branches of the unfolded protein response (UPR). However, the underlying mechanism of action of this EnR resident protein TMEM33 and the cellular functions that it regulates remain largely unknown. In this study, we show that overexpression of TMEM33 induces robust cell death in breast cancer cells. Inhibition of the PERK/eIF2alpha pathway with eIF2alpha inhibitor ISRIB blocks the TMEM33 induced cell death. TMEM33 overexpression strongly activates UPR associated pro-death JNK-p53 signaling. We also observed a significant inhibition of the downstream survivin, which blocks cell death activation by binding to caspases and inhibiting their activation. We further show that the blockage of JNK activation with either an inhibitor or overexpression of survivin, protects cells against TMEM33 induced apoptosis. In addition, we show that TMEM33 overexpression induces autophagy in breast cancer cells. Inhibition of autophagy with using either the inhibitor chloroquine or knockdown of the Atg5 gene, further sensitizes breast cancer cells to the effects of TMEM33 overexpression. Cell death induced by TMEM33 is also decreased by overexpression of the autophagy gene Beclin 1. The findings in this study demonstrate that the novel EnR resident protein TMEM33 induces cell death by activating IRE1α-JNK-p53-survivin signaling in breast cancer cells. Concurrently, autophagy is also activated by TMEM33, and functions as a pro-survival mechanism. Cell fate reflects the balance between the pro-death and pro-survival activities as regulated by TMEM33. Citation Format: Rong Hu, Xiyuan Zhang, Leena Hilakivi-Clarke, Usha Kasid, Robert Clarke. TMEM33 induces apoptosis via UPR signaling and autophagy in breast cancer 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 2329. doi:10.1158/1538-7445.AM2017-2329
Abstract 5434: Tumor necrosis factor receptor-associated protein 1 (TRAP1) as a potential target for glutamine addicted cancer cells
Authors: Vu T. Vo, Ai N. Phan, Tuyen N. Hua, Yangsik Jeong, Byoung Heon Kang, Hyun-Won Kim, Jong-Whan Choi
Journal: Cancer Research (2017)

Abstract Glutamine, a non-essential amino acid, is an important nutrient which is involved in many biochemical pathways such as energy production, macromolecular synthesis, and oxidative stress scavenging. Glutamine metabolism is dysregulated in many cancers which mostly display glutamine addiction for cell proliferation. Thus, glutamine metabolism has become a potential target for treating cancer. Here we report that glutamine-dependent cancer cells are more susceptible for inhibiting cell proliferation with inhibitor treatment of Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1), a downstream factor of oncogenic c-Myc involved in glutamine metabolism. Using cell proliferation and cell viability assays, we examined growth inhibitory effects of TRAP1 inhibitor, gamitrinib-triphenylphosphonium (G-TPP), on two groups of cell lines, glutamine-deprivation sensitive versus resistant cell lines. Included are cell lines for each group: HCC827 acquired gefitinib resistance and A549 for the sensitive; HuH7 for the resistant group. Glutamine-deprivation sensitive cell lines showed significant growth inhibition with TRAP1 inhibitor treatment while the corresponding resistant group of cell lines showed no growth inhibitory effects in the same treatment condition. This suggests a potential mechanistic connection of TRAP1 to c-Myc regulation in glutamine metabolism. Taken together, this finding provides a better understanding of oncogene-driven glutamine metabolism as well as evidence that TRAP1 is a promising therapeutic target for glutamine addicted cancer cells. Citation Format: Vu T. Vo, Ai N. Phan, Tuyen N. Hua, Yangsik Jeong, Byoung Heon Kang, Hyun-Won Kim, Jong-Whan Choi. Tumor necrosis factor receptor-associated protein 1 (TRAP1) as a potential target for glutamine addicted cancer 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 5434. doi:10.1158/1538-7445.AM2017-5434
Detection of Regional Variation in Selection Intensity within Protein-Coding Genes Using DNA Sequence Polymorphism and Divergence
Authors: Zi-Ming Zhao, Michael C. Campbell, Ning Li, Daniel S.W. Lee, Zhang Zhang, Jeffrey P. Townsend
Journal: Molecular Biology and Evolution (2017)

Numerous approaches have been developed to infer natural selection based on the comparison of polymorphism within species and divergence between species. These methods are especially powerful for the detection of uniform selection operating across a gene. However, empirical analyses have demonstrated that regions of protein-coding genes exhibiting clusters of amino acid substitutions are subject to different levels of selection relative to other regions of the same gene. To quantify this heterogeneity of selection within coding sequences, we developed Model Averaged Site Selection via Poisson Random Field (MASS-PRF). MASS-PRF identifies an ensemble of intragenic clustering models for polymorphic and divergent sites. This ensemble of models is used within the Poisson Random Field framework to estimate selection intensity on a site-by-site basis. Using simulations, we demonstrate that MASS-PRF has high power to detect clusters of amino acid variants in small genic regions, can reliably estimate the probability of a variant occurring at each nucleotide site in sequence data and is robust to historical demographic trends and recombination. We applied MASS-PRF to human gene polymorphism derived from the 1,000 Genomes Project and divergence data from the common chimpanzee. On the basis of this analysis, we discovered striking regional variation in selection intensity, indicative of positive or negative selection, in well-defined domains of genes that have previously been associated with neurological processing, immunity, and reproduction. We suggest that amino acid-altering substitutions within these regions likely are or have been selectively advantageous in the human lineage, playing important roles in protein function.
Magnitude rather than number: More evidence needed
Authors: Daniel C Hyde, Yi Mou
Journal: Behavioral and Brain Sciences (2017)

Abstract Leibovich et al. do not present enough empirical support to overturn decades of work supporting a number sense nor to convince the reader that a magnitude sense provides a better explanation of the literature. Here we highlight what we feel are the main points of weakness and the types of evidence that could be provided to be more convincing.