tbuckley/cabot-search huggingface dataset:
Subgingival debridement: end point, methods and how often?
Authors: Isabelle Laleman, Simone Cortellini, Senne De Winter, Esteban Rodriguez Herrero, Christel Dekeyser, Marc Quirynen, Wim Teughels
Journal: Periodontology 2000 (2017)

Abstract Subgingival debridement is the part of nonsurgical therapy which aims to remove the biofilm without intentionally removing the cementum or subgingival calculus. The objective of this review was to describe the end point of this therapy, the different methods used and how often it should be carried out. The literature shows that several methods are currently available for subgingival debridement, namely hand instrumentation, (ultra)sonic instrumentation, laser, photodynamic therapy and air‐polishing. None of these methods seems superior to any other regarding clinical benefits or microbiological differences. However, less treatment discomfort is reported using laser, photodynamic therapy or air‐polishing compared with hand‐ and/or (ultra)sonic instrumentation. Subgingival debridement can be carried out when, during supportive periodontal therapy, pockets of 5 mm or deeper are detected.
Abstract 391: A comparative genomics approach to understanding the control of cell context dependent P53 binding
Authors: Varsha Sundaresan, Ying Li, Benedetto DiCiaccio, Victor T. Lin, Lei Zhou
Journal: Cancer Research (2017)

Abstract Cancer is considered to be a genetic disease characterized by sequential accumulation of mutations. Recent studies have provided evidence that epigenetic changes and regulatory sequence mutations could also dysregulate oncogenes and tumor suppressors. As a transcription factor, P53 is activated in response to oncogenic stress and exerts distinct anti-proliferative functions based on the stressor and cell type. Though a number of ChIP-Seq studies have identified thousands of P53 binding sites in mammalian genomes, the functionality of these binding sites remains to be established. In addition, we know little about what controls stress and cell context specific binding profile of P53. Traditionally, mutations in the coding regions of p53 have been extensively studied to gain insights on its role in cancer and to identify strategies to restore the functions of p53 in cancer cells. We hypothesize that mutations in or epigenetic silencing of functionally important P53 binding sites play an important role in tumorigenesis as well. Since functional regulatory regions tend to be more evolutionarily conserved, in this project we propose using a comparative genomics approach to identify functional P53 binding sites and determine if these regions are involved in tumorigenesis. In order to study how P53 binding following DNA damage differs between cell types, we aim to perform comparison between P53 ChIP-Seq data generated in our lab from Drosophila embryos at different developmental stages and a cell line (Kc167) as well as published datasets from mammalian stem cells and differentiated cells. Differential expression analysis using RNA-Seq exhibited that at an early stem cell-like stage there is P53-dependent induction of pro-apoptotic genes in response to DNA damage but not in the differentiated stages. We are seeking to establish functionally significant P53 binding sites by combining ChIP-Seq data and gene expression data obtained using RNA-Seq. The importance of these binding sites will be verified by CRISPR-Cas9 -mediated genome editing. We will also perform comparison studies of DNA damage-induced P53 binding in human, mouse and Drosophila to identify analogous patterns. Knowledge gained from this study will help us to understand the role of non-coding regulatory regions in tumorigenesis, and predict patient response to apoptosis inducing therapeutic agents. It may also lead to novel strategies to restore cellular sensitivity to chemotherapy or radiation. Citation Format: Varsha Sundaresan, Ying Li, Benedetto DiCiaccio, Victor T. Lin, Lei Zhou. A comparative genomics approach to understanding the control of cell context dependent P53 binding [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 391. doi:10.1158/1538-7445.AM2017-391
Abstract 251: The Rate of Myocyte Turnover in the Mouse Heart
Authors: Ewa Wybieralska, Barbara Ogorek, James Kostyla, Kazuya Isobe, Sergio Signore, Giulia Borghetti, Mark Sundman, Annarosa Leri, Marcello Rota, Jan Kajstura
Journal: Circulation Research (2013)

The accuracy of the estimations of cell turnover in the myocardium is restricted by the difficulty to obtain from histologic samples the information regarding the rate of cell proliferation, i.e., number of cells generated per unit of time. It is easy to identify the fraction of cycling cells, but this value cannot be directly converted into the number of cells generated per day. As a result, the published estimates of cell turnover in the mammalian heart vary dramatically. Here, we propose to use the cell cycle as an internal clock to introduce the time factor in the analysis of population dynamics of cardiac cells. In this novel approach the cells are exposed to two pulses of distinct thymidine analogs, separated by time T. The first pulse is performed with 5-bromo-2’-deoxyuridine (BrdU) and the second pulse with 5-ethynyl-2’-deoxyuridine (EdU). With this protocol, the number of cells that exit the S phase during time T is equal to the number of cells positive for BrdU but negative for EdU. It can be shown that, in non-synchronous population, the number of cells exiting the S phase is equal to the number of cells entering the cell cycle. Importantly, this approach does not require knowledge of the length of the cell cycle. To measure the rate of formation of cells in the myocardium, 2 month-old mice were injected with the nucleotides at 4 hour intervals and sacrified 4 hour later. The hearts were formalin-fixed and histologic sections obtained. The first nucleotide, BrdU, by was detected by immunocytochemistry, and the second, EdU, by the “click” chemistry. Myocytes and non-myocytes were distinguished by α-sarcomeric actin and cardiac troponin I staining and analyzed by confocal microscopy. Spectral analysis was employed to ensure specificity of the detected signals. The enumeration of double positive nuclei, nuclei positive for one nucleotide only, and nuclei negative for both nucleotides indicated that in the entire left ventricle (LV) ~1,250 myocytes are generated per hour. Since the mouse LV contains ~3 x 106 parenchymal cells, these data demonstrate that the entire population of myocytes can be replaced in ~180 days. Thus, our results are consistent with a relatively high turnover rate of myocytes in the mouse heart.
Abstract 2369: Transcription activators that regulate PKC-iota expression and are downstream targets of PKC-iota
Authors: Andre H. Apostolatos, Wishrawana S. Ratnayake, Tracess Smalley, Anisul Islam, Mildred Acevedo-Duncan
Journal: Cancer Research (2017)

Abstract Protein Kinase C-iota (PKC-iota) is an anti-apoptotic oncogene over-expressed in multiple cancers including prostate, ovarian, and glioma. PKC-iota is part of a cycle that helps cancer cell avoid senescence by releasing the transcription factor NFkB and promoting apoptotic resistance. PKC-iota is activated externally by factors like loss of PTEN (Paget 2012). However, while under the effect PKC-iota specific inhibitors, expression levels decreased, suggesting PKC-iota plays a role in regulating its own expression. A previous study showed the ELK1 transcription factor to be a regulator of PKC-iota (Gustafson 2003). Other transcription factors including Jun, ISGF3, PAX3, EGR1, and FOXO1 bind on or near the promoter sequence of the gene and their role in PKC-iota regulation was analyzed. Each transcription factor was systematically silenced with its own siRNA. Western Blotting revealed expression of PKC-iota in the transcription factor silenced cells determining which transcription factors are key players in regulation of PKC-iota. qPCR and microarray were performed to analyze the transcriptome of treated cells to match protein levels with mRNA levels. Targets both up and downstream of PKC-iota were analyzed to find the pathway that PKC-iota uses to help regulate itself. Citation Format: Andre H. Apostolatos, Wishrawana S. Ratnayake, Tracess Smalley, Anisul Islam, Mildred Acevedo-Duncan. Transcription activators that regulate PKC-iota expression and are downstream targets of PKC-iota [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 2369. doi:10.1158/1538-7445.AM2017-2369
Saving or Creating: Which Are We Doing When We Resuscitate Extremely Preterm Infants?
Authors: Travis N. Rieder
Journal: The American Journal of Bioethics (2017)

Neonatal intensive care units represent simultaneously one of the great success stories of modern medicine, and one of its most controversial developments. One particularly controversial issue is the resuscitation of extremely preterm infants. Physicians in the United States generally accept that they are required to resuscitate infants born as early as 25 weeks and that it is permissible to resuscitate as early as 22 weeks. In this article, I question the moral pressure to resuscitate by criticizing the idea that resuscitation in this context "saves" a human life. Our radical medical advancements have allowed us to intervene in the life of a human before it makes sense to say that such an intervention "saves" someone; rather, what the physician does in resuscitating and treating an extremely preterm infant is to take over creating it. This matters, I argue, because "rescues" are much more morally urgent than "creations."
LINAC-based intensity modulated total marrow irradiation (TMI) in addition to myeloablative fludarabine/IV busulfan conditioning prior to allogeneic stem cell transplant for high-risk hematologic malignancies: A phase I study.
Authors: Pritesh Rajni Patel, Bulent Aydogan, Dolores Mahmud, Annie Lee Oh, John G Quigley, Santosh L. Saraf, Irum Khan, Nadim Mahmud, David J Peace, Matthew Koshy, Vincenzo De Masi, Ralph R. Weichselbaum, Damiano Rondelli
Journal: Journal of Clinical Oncology (2014)

7045 Background: Total body irradiation (TBI) currently has limited use in stem cell transplant due to significant extra-hematologic toxicity. Intensity modulated total marrow irradiation (TMI) represents an innovative technique to selectively irradiate the bone marrow. We combined a fully myeloablative chemotherapy regimen with escalating doses of TMI in a Phase I trial in allogeneic stem cell transplant. (Id: Clinicaltrials.gov NCT00988013). Methods: A Phase 1 trial (3+3 design) for adult patients with high risk (HR) hematologic malignancies enrolled 14 patients who were transplanted from related (n=9) or unrelated (n=5) donors and included: HR acute lymphoblastic (ALL) (n=2) or myeloid (AML) (n=9) leukemia, HR multiple myeloma (n=2) and chronic myeloid leukemia (CML) (n=1) resistant to TKI. Median age was 52 years (range 20-65). Patients received fludarabine 160mg/m2, targeted i.v. busulfan (AUC 4800 μM/min) and IM-TMI (from 3 to 12 Gy). Dose Limiting Toxicity was defined as any grade 3 or 4 toxicity up to day +30 on the Bearman scale. Results: Of 14 patients, 3 were enrolled in cohorts 1 (3Gy) and 2 (6Gy), 6 in cohort 3 (9Gy) and 2 in cohort 4 (12Gy). All patients engrafted. Median time for ANC >0.5 and platelets > 20 x 109/L were 15 and 15.5 days, respectively. No patient experienced grade 3 or 4 toxicity before day +30. Grade 1-2 mucositis was observed in all patients. After a median follow up of 598 days (range 68-1319 days), 7 patients are alive and 6 remain in remission. Cause of death was TRM (after D30) (n=4: pneumonia, liver failure, GVHD and sepsis), all in cohorts 3 and 4 and relapse (n=3). Cohort 4 was terminated after 2 patients experienced significant toxicity and prolonged hospitalization. Lymphocyte reconstitution at 1, 3 and 6 mo was comparable among the groups. Conclusions: This is the first study showing that TMI can be safely combined with fully myeloablative chemotherapy. A dose of 9 Gy TMI will be utilized in a Phase II study. Linac based TMI can potentially be replicated in every transplant center and exploited in new autologous or allogeneic stem cell transplantation studies. Clinical trial information: NCT00988013.
Abstract 2379: Nuclear lemur tyrosine kinase-2 regulates RNA polymerase II dependent transcription in prostate cancer
Authors: Kalpit Shah, Justin Foley, Michael L. Nickerson, Michael Dean, Neil Bradbury
Journal: Cancer Research (2017)

Abstract The Androgen Receptor (AR), a DNA-binding transcription factor plays a key role in the development and maintenance of prostate epithelia by modulating expression of growth-promoting genes. AR has been proposed to regulate gene expression by enhancing the efficiency of RNA polymerase II (RNAPII) dependent transcription elongation. Dysregulation of this AR-dependent transcriptional activity has been implicated not only in prostate cancer but also androgen-independent prostate cancer. Recently, we showed that protein expression of Lemur Tyrosine Kianse-2 (LMTK2), a serine-threonine kinase is downregulated in prostate cancer. Importantly, our study ascribed a novel role for LMTK2, as a negative regulator of AR-dependent transcriptional activity in prostate epithelial cells. However, the mechanism through which LMTK2 is able to regulate AR remains to be determined. Here, we show that LMTK2 is not only present in cytoplasmic fraction but also, within the nucleus of mammalian cells where it co-localizes with AR, newly transcribed mRNA and with RNA polymerase II (RNAPII). Interestingly, our data reveals that LMTK2 colocalizes with elongating RNAPII, phosphorylated on serine 2 of the carboxyl-terminal domain. This presents an interesting possibility that LMTK2 might be able to regulate transcription of AR-dependent genes by interacting with the elongating RNAPII and transcription &amp; epigenetic factors. As such, our study potentially identifies LMTK2 as an important player regulating the AR-RNAPII mediated transcription machinery in mammalian cells. Citation Format: Kalpit Shah, Justin Foley, Michael L. Nickerson, Michael Dean, Neil Bradbury. Nuclear lemur tyrosine kinase-2 regulates RNA polymerase II dependent transcription in prostate cancer [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 2379. doi:10.1158/1538-7445.AM2017-2379
Abstract 2392: A multiplex histone H3 PTM assay for epigenetic biomarker discovery in tissue biopsy and archived clinical samples
Authors: Mary Anne Jelinek, Melissa Ritland, AJ Westergren
Journal: Cancer Research (2017)

Abstract Dysregulation of epigenetic mechanisms is known to play an important role in the development and progression of cancer. One such mechanism is manifested as altered levels of histone modifications involved in regulating gene transcription. N-terminal histone tails can have a variety of modifications, such as phosphorylation, methylation and acetylation at specific amino acid residues which are conserved throughout eukaryotes and function by altering chromatin structure and creating binding sites for chromatin readers, writers or erasers. Numerous studies have reported aberrant global levels of several histone H3 and H4 post-translational modifications (PTMs) in a wide range of solid tumor types. These changes have been shown to be predictive of clinical outcome, raising the possibility that histone modifications have potential as epigenetic biomarkers. Clinical samples have immense potential for biomarker identification since they are often accompanied with valuable information pertaining to patient history, treatment courses and disease outcome. The preferred method for clinical sample preservation is formalin-fixation followed by paraffin embedding (FFPE). While extraction and downstream analysis of DNA and RNA from FFPE samples is now routine, proteomic studies of FFPE samples is hampered by extensive protein cross-linking generated by formalin fixation. Analysis of histone PTMs in patient archival samples is limited to low-throughput immunohistochemical staining, and is not an ideal approach for mining large sample cohorts for biomarker identification. Western blot or ELISA methods, which have large sample requirements, are simply not an option for FFPE samples. We have developed a multiplex bead-based ELISA assay which enables simultaneous interrogation of thirteen histone H3 PTMs. The assay is performed in 96-well plates and is ideally suited for profiling histone modification levels in limiting or small samples. We will present the application of this technology in a variety of sample types including frozen tissue, formaldehyde-cross linked cells and tissues, and in small molecule inhibitor screens with as few as 2,000 cells per well. The ability to simultaneous detect up to thirteen histone H3 PTMs provides a unique feature that enables determination of for on-target and off-target effects within the same sample. Citation Format: Mary Anne Jelinek, Melissa Ritland, AJ Westergren. A multiplex histone H3 PTM assay for epigenetic biomarker discovery in tissue biopsy and archived clinical samples [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 2392. doi:10.1158/1538-7445.AM2017-2392
Recent advances in uveal melanoma treatment
Authors: Beatriz Álvarez‐Rodríguez, Alfonso Latorre, Christian Posch, Álvaro Somoza
Journal: Medicinal Research Reviews (2017)

Abstract Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Recent advances in the understanding of molecular characteristics helped to determine which tumors are most likely to progress. About 50% of patients carrying genetic alterations such as chromosomal aberrations and mutations are at significant risk for metastatic disease of which the majority will succumb to UM within few months. Currently, there is no effective treatment for metastatic uveal melanoma, and we hope this review will encourage researchers and clinicians to work to find a better standard of care. In this article we provide a comprehensive overview of the molecular framework of UM, highlighting the most common mutations involved in this kind of cancer. It also covers the most recent treatments from basic research to clinical trials, including small molecules, nucleic acids or immunotherapy, among others. It is intended to serve as a key reference for clinicians and researchers working in this field.
A Phase 1 study to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activities of daily oral BAL101553, a novel tumor checkpoint controller (TCC) in adult patients with advanced solid tumors.
Authors: Rebecca Sophie Kristeleit, T.R. Jeffry Evans, Juanita Lopez, Sarah Slater, Manolo D'Arcangelo, Yvette Drew, Sola Adeleke, Jessica Brown, Donna Crawford, Nikolaos Diamantis, Paul Gougis, Alexandar Tzankov, Alison L. Hannah, Stephanie Anderson, Heidi A Lane, Anne Schmitt-Hoffmann, Martina Maurer, Felix Bachmann, Marc Frederick Engelhardt, Elizabeth R. Plummer
Journal: Journal of Clinical Oncology (2016)

TPS2594 Background: BAL101553 is the pro-drug of BAL27862, a novel small molecule TCC that promotes tumor cell death by modulating the spindle assembly checkpoint (SAC). In a completed Phase 1 (P1) study, pre- and post-treatment tumor biopsies revealed antiproliferative and vascular disrupting PD effects with BAL101553 administered as a 2-hour intravenous infusion1. The time profile of transient blood pressure elevations linked the vascular effects of the drug to Cmax, while preclinical data suggest that effects on tumor cell proliferation are AUC-mediated; vascular toxicity was dose-limiting. Given this, dosing strategies that optimize the PK/PD profile, particularly those that minimize the Cmax, may allow higher doses and/or exposures of BAL27862 to be tolerated. Preclinical data with oral BAL101553 in various animal models, including colorectal, lung cancer and glioblastoma xenograft models, suggest excellent bioavailability and antitumor efficacy. Methods: This is an ongoing multicenter, open-label, Phase 1 dose-escalation study (NCT02490800) using a 3+3 design to determine the maximum tolerated dose (MTD), characterize dose-limiting toxicities (DLTs) and assess the PK, PD and antitumor activities of oral BAL101553. Eligible patients with advanced solid tumors, having failed standard therapy, receive once-daily oral capsules of BAL101553 in consecutive 28-day cycles. Adverse events are assessed using CTCAEv4; objective tumor response by RECIST 1.1 (every 2 cycles). The starting dose is 2 mg per day and dose escalation allows for dose doubling depending on observed toxicities. PD assessments include tumor biopsies and circulating tumor, endothelial and endothelial progenitor cells (CTCs, CECs, CEPs). Tumor biomarkers analyzed include BubR1, a checkpoint protein involved in the SAC and a potential biomarker for BAL101553 activity. Time-concentration PK profiles and repeated trough levels are assessed throughout the first two treatment cycles. 1Molife LR et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 2562) Clinical trial information: NCT02490800.
Abstract 1970: Glucose-regulated protein 94 is the novel progression biomarker in esophageal squamous cell carcinoma
Authors: Yu-Jia Chang, Chien-Yu Huang
Journal: Cancer Research (2017)

Abstract Background Esophageal cancer is a worldwide health problem with a very poor prognosis as most patients present very late when the disease is advanced and difficult to cure. It is urgent to figure out a diagnostic and therapeutic strategy. Glucose-regulated protein 94 (GRP94) has been found highly correlation with cancer progression. However, the role of GRP94 in the progression and metastasis of esophageal squamous cell carcinoma (ESCC) is still unclear. Methods: We investigated the GRP94 expression level of ESCC cells and generated GRP94-KD cells by shRNA technique. The proliferation assay, migration, invasion assay were performed. The tissue array was performed to see the correlation of GRP94 and clinical outcome on ESCC. Mitochondrial bioenergetics were assessed using a Seahorse XF24 flux analyzer. The Transmission Electron microscopy was applied to see the structure of mitochondria. Results: We found that ESCC specimen that expressed higher GRP94 showed the lower overall survival in tissue array results. The ESCC cells expressed high level of GRP94. Silencing GRP94 reduced the proliferation, migratory and invasion activity. Transmission Electron microscopy revealed the impaired mitochondrial in GRP94-KD cells. GRP94-KD cells also displayed reduced basal respiration, spare of respiratory capacity and ATP production. GRP94-KD caused the accumulation of oxidative damage. In molecular mechanism, we found that silencing GRP94 may cause a decrease COX2 expression and alter EMT expression pattern. Conclusion We found that silencing GRP94 in ESCC cells suppressed cancer growth and metastasis ability through COX-2 and EMT molecules expression. In addition, GRP94 may mediate the functional mitochondria in ESCC. GRP94 may be a new target to develop the therapeutic strategy for ESCC. Citation Format: Yu-Jia Chang, Chien-Yu Huang. Glucose-regulated protein 94 is the novel progression biomarker in esophageal squamous cell 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 1970. doi:10.1158/1538-7445.AM2017-1970