tbuckley/cabot-search huggingface dataset:
Loss of Function of the Tumor Suppressor DKC1 Perturbs p27 Translation Control and Contributes to Pituitary Tumorigenesis
Authors: Cristian Bellodi, Olya Krasnykh, Nikesha Haynes, Marily Theodoropoulou, Guang Peng, Lorenzo Montanaro, Davide Ruggero
Journal: Cancer Research (2010)

Mutations in DKC1, encoding for dyskerin, a pseudouridine synthase that modifies rRNA and regulates telomerase activity, are associated with ribosomal dysfunction and increased cancer susceptibility in the human syndrome, X-linked dyskeratosis congenita (X-DC). In a mouse model for X-DC, impairments in DKC1 function affected the translation of specific mRNAs harboring internal ribosomal entry site (IRES) elements, including the tumor suppressor, p27. However, how this translational deregulation contributes to tumor initiation and progression remains poorly understood. Here, we report that impairment in p27 IRES-mediated translation due to decreased levels of DKC1 activity markedly increases spontaneous pituitary tumorigenesis in p27 heterozygous mice. Using a new bioluminescent mouse model, we monitored p27 translation in vivo and show that p27 IRES-mediated translation is reduced in the pituitary of DKC1 hypomorphic mice (DKC1(m)). Furthermore, we show that DKC1 has a critical role in regulating the assembly of the 48S translational preinitiation complex mediated by the p27 IRES element. An analysis of human tumors identified a novel mutation of DKC1 (DKC1(S485G)) in a human pituitary adenoma. We show that this specific amino acid substitution significantly alters DKC1 stability/pseudouridylation activity, and this correlates with reductions in p27 protein levels. Furthermore, DKC1(S485G) mutation does not alter telomerase RNA levels. Altogether, these findings show that genetic alterations in DKC1 could contribute to tumorigenesis associated with somatic cancers and establish a critical role for DKC1 in tumor suppression, at least in part, through translational control of p27.
Sentinel Lymph Node Biopsy for Patients With Early-Stage Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update
Authors: Gary H. Lyman, Sarah Temin, Stephen B. Edge, Lisa A. Newman, Roderick R. Turner, Donald L. Weaver, Al B. Benson, Linda D. Bosserman, Harold J. Burstein, Hiram Cody, James Hayman, Cheryl L. Perkins, Donald A. Podoloff, Armando E. Giuliano
Journal: Journal of Clinical Oncology (2014)

To provide evidence-based recommendations to practicing oncologists, surgeons, and radiation therapy clinicians to update the 2005 clinical practice guideline on the use of sentinel node biopsy (SNB) for patients with early-stage breast cancer.The American Society of Clinical Oncology convened an Update Committee of experts in medical oncology, pathology, radiation oncology, surgical oncology, guideline implementation, and advocacy. A systematic review of the literature was conducted from February 2004 to January 2013 in Medline. Guideline recommendations were based on the review of the evidence by Update Committee.This guideline update reflects changes in practice since the 2005 guideline. Nine randomized clinical trials (RCTs) met systematic review criteria for clinical questions 1 and 2; 13 cohort studies informed clinical question 3.Women without sentinel lymph node (SLN) metastases should not receive axillary lymph node dissection (ALND). Women with one to two metastatic SLNs planning to undergo breast-conserving surgery with whole-breast radiotherapy should not undergo ALND (in most cases). Women with SLN metastases who will undergo mastectomy should be offered ALND. These three recommendation are based on RCTs. Women with operable breast cancer and multicentric tumors, with ductal carcinoma in situ (DCIS) who will undergo mastectomy, who previously underwent breast and/or axillary surgery, or who received preoperative/neoadjuvant systemic therapy may be offered SNB. Women who have large or locally advanced invasive breast cancer (tumor size T3/T4), inflammatory breast cancer, or DCIS (when breast-conserving surgery is planned) or are pregnant should not undergo SNB. These recommendations are based on cohort studies and/or informal consensus. In some cases, updated evidence was insufficient to update previous recommendations.
Cd1d–Glycolipid Tetramers
Authors: H. Robson MacDonald
Journal: The Journal of Experimental Medicine (2000)

Natural killer (NK) T cells are a subset of mature T lymphocytes that express an α/β TCR together with markers characteristic of NK cells such as NK1.1 ([1][1])([2][2]). In contrast to conventional T cells, which recognize small peptides bound to polymorphic MHC class I or class II molecules, TCRs
Sites and sizes of fat deposits around the pharynx in obese patients with obstructive sleep apnoea and weight matched controls
Authors: RL Horner, RH Mohiaddin, DG Lowell, SA Shea, ED Burman, DB Longmore, A Guz
Journal: European Respiratory Journal (1989)

It has been suggested that deposition of fat in the soft tissues surrounding the upper airway may be an important factor in the pathogenesis of obstructive sleep apnoea (OSA) in obese subjects. We have used magnetic resonance imaging to determine the site(s) and size(s) of fat deposits around the upper airway in six obese patients with OSA (116-153% of ideal body weight) and five weight-matched controls without OSA (107-152% of ideal body weight). In all subjects, large deposits of fat were present postero-lateral to the oropharyngeal airspace at the level of the soft palate. Significantly more fat was present in these regions in the patients with OSA (p = 0.03). Fat deposits in the soft palate were observed in 4 of the 6 patients with OSA but none of the controls. Fatty streaks were observed in the tongue in 2 of the 5 controls and 3 of the 6 patients with OSA. Fat deposits were observed anterior to the laryngopharyngeal airspace, in submental regions, in all obese subjects. This study shows that more fat is present in those areas surrounding the collapsable segment of the pharynx in patients with OSA, compared to equally obese control subjects without OSA.
Histone Deacetylase Inhibitors: Inducers of Differentiation or Apoptosis of Transformed Cells
Authors: P. A. Marks, V. M. Richon, R. A. Rifkind
Journal: JNCI Journal of the National Cancer Institute (2000)

Histone deacetylase (HDAC) inhibitors have been shown to be potent inducers of growth arrest, differentiation, and/or apoptotic cell death of transformed cells in vitro and in vivo. One class of HDAC inhibitors, hydroxamic acid-based hybrid polar compounds (HPCs), induce differentiation at micromolar or lower concentrations. Studies (x-ray crystallographic) showed that the catalytic site of HDAC has a tubular structure with a zinc atom at its base and that these HDAC inhibitors, such as suberoylanilide hydroxamic acid and trichostatin A, fit into this structure with the hydroxamic moiety of the inhibitor binding to the zinc. HDAC inhibitors cause acetylated histones to accumulate in both tumor and normal tissues, and this accumulation can be used as a marker of the biologic activity of the HDAC inhibitors. Hydroxamic acid-based HPCs act selectively to inhibit tumor cell growth at levels that have little or no toxicity for normal cells. These compounds also act selectively on gene expression, altering the expression of only about 2% of the genes expressed in cultured tumor cells. In general, chromatin fractions enriched in actively transcribed genes are also enriched in highly acetylated core histones, whereas silent genes are associated with nucleosomes with a low level of acetylation. However, HDACs can also acetylate proteins other than histones in nucleosomes. The role that these other targets play in the induction of cell growth arrest, differentiation, and/or apoptotic cell death has not been determined. Our working hypothesis is that inhibition of HDAC activity leads to the modulation of expression of a specific set of genes that, in turn, result in growth arrest, differentiation, and/or apoptotic cell death. The hydroxamic acid-based HPCs are potentially effective agents for cancer therapy and, possibly, cancer chemoprevention.
Sex steroid blockade enhances thymopoiesis by modulating Notch signaling
Authors: Enrico Velardi, Jennifer J. Tsai, Amanda M. Holland, Tobias Wertheimer, Vionnie W.C. Yu, Johannes L. Zakrzewski, Andrea Z. Tuckett, Natalie V. Singer, Mallory L. West, Odette M. Smith, Lauren F. Young, Fabiana M. Kreines, Emily R. Levy, Richard L. Boyd, David T. Scadden, Jarrod A. Dudakov, Marcel R.M. van den Brink
Journal: The Journal of Experimental Medicine (2014)

Paradoxical to its importance for generating a diverse T cell repertoire, thymic function progressively declines throughout life. This process has been at least partially attributed to the effects of sex steroids, and their removal promotes enhanced thymopoiesis and recovery from immune injury. We show that one mechanism by which sex steroids influence thymopoiesis is through direct inhibition in cortical thymic epithelial cells (cTECs) of Delta-like 4 (Dll4), a Notch ligand crucial for the commitment and differentiation of T cell progenitors in a dose-dependent manner. Consistent with this, sex steroid ablation (SSA) led to increased expression of Dll4 and its downstream targets. Importantly, SSA induced by luteinizing hormone-releasing hormone (LHRH) receptor antagonism bypassed the surge in sex steroids caused by LHRH agonists, the gold standard for clinical ablation of sex steroids, thereby facilitating increased Dll4 expression and more rapid promotion of thymopoiesis. Collectively, these findings not only reveal a novel mechanism underlying improved thymic regeneration upon SSA but also offer an improved clinical strategy for successfully boosting immune function.
Mitogen-Activated Protein (MAP) Kinase/MAP Kinase Phosphatase Regulation: Roles in Cell Growth, Death, and Cancer
Authors: Tarek Boutros, Eric Chevet, Peter Metrakos
Journal: Pharmacological Reviews (2008)

Mitogen-activated protein kinase dual-specificity phosphatase-1 (also called MKP-1, DUSP1, ERP, CL100, HVH1, PTPN10, and 3CH134) is a member of the threonine-tyrosine dual-specificity phosphatases, one of more than 100 protein tyrosine phosphatases. It was first identified approximately 20 years ago, and since that time extensive investigations into both mkp-1 mRNA and protein regulation and function in different cells, tissues, and organs have been conducted. However, no general review on the topic of MKP-1 exists. As the subject matter pertaining to MKP-1 encompasses many branches of the biomedical field, we focus on the role of this protein in cancer development and progression, highlighting the potential role of the mitogen-activated protein kinase (MAPK) family. Section II of this article elucidates the MAPK family cross-talk. Section III reviews the structure of the <i>mkp-1</i> encoding gene, and the known mechanisms regulating the expression and activity of the protein. Section IV is an overview of the MAPK-specific dual-specificity phosphatases and their role in cancer. In sections V and VI, mkp-1 mRNA and protein are examined in relation to cancer biology, therapeutics, and clinical studies, including a discussion of the potential role of the MAPK family. We conclude by proposing an integrated scheme for MKP-1 and MAPK in cancer.
The phylogeny of land plants inferred from 18S rDNA sequences: pushing the limits of rDNA signal?
Authors: P. S. Soltis, D. E. Soltis, P. G. Wolf, D. L. Nickrent, S. M. Chaw, R. L. Chapman
Journal: Molecular Biology and Evolution (1999)

Previous studies of the phylogeny of land plants based on analysis of 18S ribosomal DNA (rDNA) sequences have generally found weak support for the relationships recovered and at least some obviously spurious relationships, resulting in equivocal inferences of land plant phylogeny. We hypothesized that greater sampling of both characters and taxa would improve inferences of land plant phylogeny based on 18S rDNA sequences. We therefore conducted a phylogenetic analysis of complete (or nearly complete) 18S rDNA sequences for 93 species of land plants and 7 green algal relatives. Parsimony analyses with equal weighting of characters and characters state changes and parsimony analyses weighting (1) stem bases half as much as loop bases and (2) transitions half as much as transversions did not produce substantially different topologies. Although the general structure of the shortest trees is consistent with most hypotheses of land plant phylogeny, several relationships, particularly among major groups of land plants, appear spurious. Increased character and taxon sampling did not substantially improve the performance of 18S rDNA in phylogenetic analyses of land plants, nor did analyses designed to accommodate variation in evolutionary rates among sites. The rate and pattern of 18S rDNA evolution across land plants may limit the usefulness of this gene for phylogeny reconstruction at deep levels of plant phylogeny. We conclude that the mosaic structure of 18S rDNA, consisting of highly conserved and highly variable regions, may contain historical signal at two levels. Rapidly evolving regions are informative for relatively recent divergences (e.g., within angiosperms, seed plants, and ferns), but homoplasy at these sites makes it difficult to resolve relationships among these groups. At deeper levels, changes in the highly conserved regions of small-subunit rDNAs provide signal across all of life. Because constraints imposed by the secondary structure of the rRNA may affect the phylogenetic information content of 18S rDNA, we suggest that 18S rDNA sequences be combined with other data and that methods of analysis be employed to accommodate these differences in evolutionary patterns, particularly across deep divergences in the tree of life.
The transcription factor NFATc2 controls IL-6–dependent T cell activation in experimental colitis
Authors: Benno Weigmann, Hans A. Lehr, George Yancopoulos, David Valenzuela, Andrew Murphy, Sean Stevens, Jan Schmidt, Peter R. Galle, Stefan Rose-John, Markus F. Neurath
Journal: The Journal of Experimental Medicine (2008)

The nuclear factor of activated T cells (NFAT) family of transcription factors controls calcium signaling in T lymphocytes. In this study, we have identified a crucial regulatory role of the transcription factor NFATc2 in T cell–dependent experimental colitis. Similar to ulcerative colitis in humans, the expression of NFATc2 was up-regulated in oxazolone-induced chronic intestinal inflammation. Furthermore, NFATc2 deficiency suppressed colitis induced by oxazolone administration. This finding was associated with enhanced T cell apoptosis in the lamina propria and strikingly reduced production of IL-6, -13, and -17 by mucosal T lymphocytes. Further studies using knockout mice showed that IL-6, rather than IL-23 and -17, are essential for oxazolone colitis induction. Administration of hyper-IL-6 blocked the protective effects of NFATc2 deficiency in experimental colitis, suggesting that IL-6 signal transduction plays a major pathogenic role in vivo. Finally, adoptive transfer of IL-6 and wild-type T cells demonstrated that oxazolone colitis is critically dependent on IL-6 production by T cells. Collectively, these results define a unique regulatory role for NFATc2 in colitis by controlling mucosal T cell activation in an IL-6–dependent manner. NFATc2 in T cells thus emerges as a potentially new therapeutic target for inflammatory bowel diseases.
Abstract 3858: Implications of the downregulation of stemness/reprogramming factor expression by ibuprofen and biguanides
Authors: Laura Grenlin, Tuan-Anh Tran, Sarah Lomahan, Naohiko Ikegaki, Xao X. Tang
Journal: Cancer Research (2014)

Abstract Cancer stem cells (CSCs) are thought to have the capacity to renew indefinitely, to initiate tumor formation, and to give rise to multiple non-tumorigenic progenies via asymmetric cell division. As a result of this phenotypic drift, an established tumor would consist of a mixture of CSC and non-CSC. Based on the current view, the CSC population is likely responsible for distant metastases, drug resistance and recurrence. However, the process by which this cell population is generated in a tumor mass has continued to be unclear. Based on our previous study (PNAS Vol. 110: 6097-6102, 2013), this process may involve nuclear reprogramming, namely the elevated expression of stemness/reprogramming factors (SOX2, OCT4, NANOG, LIN28, KLF4, MYC/MYCN, and those with equivalent functions). If so, it is conceivable that destabilization of these proteins would prevent or substantially slow down the generation of CSC compartment(s) within a tumor mass. Recently, we have reported that anti-inflammatory Ibuprofen and anti-diabetic biguanides destabilize MYC and MYCN in neuroblastoma cells. In this study, we have investigated the effects of Ibuprofen and Phenformin on stemness phenotypes of cancer cells (i.e., the expression of stemness factors) using the teratocarcinoma cell line NT2. NT2 cells were chosen as the experimental system because unlike many other cancer cell lines, they retain the expression of stemness/reprogramming factors. Furthermore, they express both MYC and MYCN proteins. Our data showed that high-dose/short-term treatment of NT2 cells with Phenformin and Ibuprofen significantly down-regulated the expression of MYC/MYCN, OCT4, SOX2, and NANOG. Moreover, the anti-stemness effect of Ibuprofen in the low-dose/long-term treatment was also evident (0.15 mM at Day 7 of the drug-treatment or 0.15 mM and 0.25 mM at Day 4). Experiments are underway to address the similar effect of low-dose/long-term treatment of Metformin and Phenformin in NT2 cells. We are also investigating a change in global gene expression in the drugs-treated NT2 cells, with the emphasis on stem cell-related genes and pathways. Results of these studies will help us better understand how these common drugs (anti-inflammation and diabetes medications) can be used in anti-cancer therapeutics, and more importantly, in cancer prevention, which is the key to eradication of this disease. Citation Format: Laura Grenlin, Tuan-Anh Tran, Sarah Lomahan, Naohiko Ikegaki, Xao X. Tang. Implications of the downregulation of stemness/reprogramming factor expression by ibuprofen and biguanides. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3858. doi:10.1158/1538-7445.AM2014-3858
Single-Step Antigen Loading and Activation of Dendritic Cells by mRNA Electroporation for the Purpose of Therapeutic Vaccination in Melanoma Patients
Authors: Aude Bonehill, An M.T. Van Nuffel, Jurgen Corthals, Sandra Tuyaerts, Carlo Heirman, Violaine François, Didier Colau, Pierre van der Bruggen, Bart Neyns, Kris Thielemans
Journal: Clinical Cancer Research (2009)

A critical factor determining the effectiveness of currently used dendritic cell (DC)-based vaccines is the DC activation or maturation status. We have recently shown that the T-cell stimulatory capacity of DCs pulsed with tumor-antigen-derived peptides can be considerably increased by activating the DCs through electroporation with mRNA encoding CD40 ligand, CD70, and a constitutively active Toll-like receptor 4 (TriMix DCs). Here, we investigate whether TriMix DCs can be coelectroporated with whole tumor-antigen-encoding mRNA.The T-cell stimulatory capacity of TriMix DCs pulsed with the immunodominant MelanA-A2 peptide and that of TriMix DCs coelectroporated with MelanA mRNA were compared in vitro. TriMix DCs were also coelectroporated with mRNA encoding Mage-A3, Mage-C2, tyrosinase, or gp100. The capacity of these DCs to stimulate tumor-antigen-specific T cells in melanoma patients was investigated both in vitro before vaccination and after DC vaccination.Like peptide-pulsed TriMix DCs, TriMix DCs coelectroporated with MelanA mRNA are very potent in inducing MelanA-specific CD8(+) T cells in vitro. These T cells have an activated phenotype, show cytolytic capacity, and produce inflammatory cytokines in response to specific stimulation. TriMix DCs coelectroporated with tyrosinase are able to stimulate tyrosinase-specific CD8(+) T cells in vitro from the blood of nonvaccinated melanoma patients. Furthermore, TriMix DCs coelectroporated with Mage-A3, Mage-C2, or tyrosinase are able to induce antigen-specific CD8(+) T cells through therapeutic DC vaccination.TriMix DCs coelectroporated with whole tumor-antigen mRNA stimulate antigen-specific T cells in vitro and induce antigen-specific T-cell responses in melanoma patients through vaccination. Therefore, they represent a promising new approach for antitumor immunotherapy.
The Dark Side of Extracellular ATP in Kidney Diseases
Authors: Anna Solini, Vera Usuelli, Paolo Fiorina
Journal: Journal of the American Society of Nephrology (2014)

Intracellular ATP is the most vital source of cellular energy for biologic systems, whereas extracellular ATP is a multifaceted mediator of several cell functions via its interaction, in an autocrine or paracrine manner, with P2 purinergic receptors expressed on the cell surface. These ionotropic and metabotropic P2 purinergic receptors modulate a variety of physiologic events upon the maintenance of a highly sensitive “set point,” the derangement of which may lead to the development of key pathogenic mechanisms during acute and chronic diseases. Growing evidence suggests that extracellular ATP signaling via P2 purinergic receptors may be involved in different renal pathologic conditions. For these reasons, investigators and pharmaceutical companies are actively exploring novel strategies to antagonize or block these receptors with the goal of reducing extracellular ATP production or accelerating extracellular ATP clearance. Targeting extracellular ATP signaling, particularly through the P2X7 receptor, has considerable translational potential, given that novel P2X7-receptor inhibitors are already available for clinical use (e.g., CE224,535, AZD9056, and GSK1482160). This review summarizes the current evidence regarding the involvement of extracellular ATP and its P2 purinergic receptor–mediated signaling in physiologic and pathologic processes in the kidney; potential therapeutic options targeting extracellular ATP purinergic receptors are analyzed as well.
Activated parathyroid hormone/parathyroid hormone–related protein receptor in osteoblastic cells differentially affects cortical and trabecular bone
Authors: L.M. Calvi, N.A. Sims, J.L. Hunzelman, M.C. Knight, A. Giovannetti, J.M. Saxton, H.M. Kronenberg, R. Baron, E. Schipani
Journal: Journal of Clinical Investigation (2001)

Parathyroid hormone (PTH), an important regulator of calcium homeostasis, targets most of its complex actions in bone to cells of the osteoblast lineage. Furthermore, PTH is known to stimulate osteoclastogenesis indirectly through activation of osteoblastic cells. To assess the role of the PTH/PTH-related protein receptor (PPR) in mediating the diverse actions of PTH on bone in vivo, we generated mice that express, in cells of the osteoblastic lineage, one of the constitutively active receptors described in Jansen’s metaphyseal chondrodysplasia. In these transgenic mice, osteoblastic function was increased in the trabecular and endosteal compartments, whereas it was decreased in the periosteum. In trabecular bone of the transgenic mice, there was an increase in osteoblast precursors, as well as in mature osteoblasts. Osteoblastic expression of the constitutively active PPR induced a dramatic increase in osteoclast number in both trabecular and compact bone in transgenic animals. The net effect of these actions was a substantial increase in trabecular bone volume and a decrease in cortical bone thickness of the long bones. These findings, for the first time to our knowledge, identify the PPR as a crucial mediator of both bone-forming and bone-resorbing actions of PTH, and they underline the complexity and heterogeneity of the osteoblast population and/or their regulatory microenvironment.