tbuckley/cabot-search huggingface dataset:
Failing to meet the goals of periodontal recall programs. What next?
Authors: Giles McCracken, Abisola Asuni, Mark Ritchie, Christopher Vernazza, Peter Heasman
Journal: Periodontology 2000 (2017)

Supportive periodontal care is a crucial aspect of the management of chronic periodontitis and peri-implantitis and is inevitably a long-term commitment for both the clinician and the patient. The principal goals of supportive care are to achieve a high standard of plaque control, minimize bleeding and maintain pockets at less than 6 mm. Gain of attachment around natural teeth during supportive periodontal care has been reported, although gain of attachment and of bone during supportive care may be a more pragmatic and aspirational aim in the longer term. Furthermore, we occasionally see patients for whom, despite excellent home and professional care (surgical or nonsurgical), including the management of risk factors, supportive periodontal care appears to be failing and therefore for such patients the clinician needs to consider further management options. This review considers, in particular, the options of using local or systemically delivered antimicrobials to eradicate periodontal and peri-implant disease progression and discusses the extent to which culture and sensitivity testing before the prescription of systemically delivered antimicrobials may be a cost-effective alternative to prescribing 'blind'.
Abstract 3180: Chemotherapeutical agent triggers transient resistance of cancer cells by promoting ABCB1 intercellular transfer
Authors: Xiaokun Wang, Dongjuan Qiao, Likun Chen, Liyan Huang, Meng Xu, Zhen Chen, Fang Wang, Zhesheng Chen, Musheng Zeng, Li-Wu Fu
Journal: Cancer Research (2017)

Abstract Multidrug resistance remains a major impediment to successful chemotherapy. In clinical chemotherapy, some patients often develop chemoresistance quite rapidly, the underlying mechanism remains elusive. Herein, we report that a transient exposure to chemotherapeutic agents can acutely promote the intercellular transfer of ABCB1 through stimulating Rab8B-mediated secretion of microvesicles (MVs) containing ABCB1 in drug-resistant donor cells, and promoting parallelly the endocytic recycling of ABCB1 in recipient tumor cells via the downregulation of Rab5. Sensitive recipient cells take up these ABCB1-incorporated MVs by a clathrin- and dynamin 2- dependent endocytic pathway, thereby acquiring a transient resistance to chemotherapeutic agents which are ABCB1 substrates. More fascinatingly, ABCB1 molecules can locally or distantly transfer to recipient tumor cells and respond to chemotherapeutical drug in the xenograft tumor models. In some cases of patients with NSCLC, a variable increase of ABCB1 surface expression was also detected in the peripheral blood monocyte subpopulations after they received the first chemotherapy. Our findings proposed a novel molecular mechanism of how sensitive cancer cells rapidly acquire the emergency resistance to chemotherapeutic agents by stimulating intercellular transfer of ABCB1. The precise modulation of this process may provide a valid therapeutic strategy to alleviate the MDR phenotype for successful treatment. Citation Format: Xiaokun Wang, Dongjuan Qiao, Likun Chen, Liyan Huang, Meng Xu, Zhen Chen, Fang Wang, Zhesheng Chen, Musheng Zeng, Li-Wu Fu. Chemotherapeutical agent triggers transient resistance of cancer cells by promoting ABCB1 intercellular transfer [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 3180. doi:10.1158/1538-7445.AM2017-3180
Abstract 1811: A PEAK1/GATA2 signaling axis controls VEGFR2 expression to mediate angiogenesis
Authors: Richard L. Klemke
Journal: Cancer Research (2017)

Abstract Formation of new blood vessels (angiogenesis) is crucial for proper development, but can also contribute to many diseases including cancer. Vascular endothelial growth factor receptor 2 (VEGFR2) is a receptor tyrosine kinase that mediates angiogenesis in developing vertebrates and is frequently upregulated in many human cancers. However, the underlying mechanisms that regulate VEGFR2 expression in normal and diseased cells are poorly understood. Here we demonstrate that pseudopodium-enriched atypical kinase 1 (PEAK1) mediates developmental and tumor-induced angiogenesis by modulating VEGFR2 expression and downstream signaling. Knockout of peak1 in zebrafish using TALEN technology (Transcription Activator-Like Effector Nucleases) or knockdown by specific peak1 morpholinos (MO) induced severe pericardial edema, blood-pooling defects, and inhibited formation of intersegmental (ISV) and subintestinal vessels (SIV). In Peak1 knockout mice, neonatal retinal vessel development was severely delayed, and the ex vivo angiogenic ability of adult thoracic aorta was greatly reduced. Intravital time-lapse imaging of ISV formation in peak1 knockout zebrafish revealed major defects in endothelial cell migration and proliferation. Similarly, PEAK1 knockdown or overexpression in HUVECs modulated endothelial cell migration, proliferation, and vessel sprouting in vitro. Biochemical studies and quantitative proteomic profiling of PEAK1 knockdown HUVECs revealed a dramatic loss of VEGFR2 mRNA and protein expression, which attenuated downstream signaling to Akt and ERK, leading to loss of VEGF-mediated vessel formation. PEAK1 specifically regulated VEGFR2 levels and did not alter VEGFR1 expression, and reconstitution of PEAK1 knockdown cells with PEAK1 restored VEGFR2 mRNA and protein expression. Mechanistic studies revealed that PEAK1 specifically regulates VEGFR2 mRNA transcription by modulating expression of the transcription factor GATA2. Re-expression of GATA2 in PEAK1 depleted cells restored VEGFR2 mRNA and protein expression as well as downstream signaling, indicating that GATA2 is a necessary downstream component in this response. Also, introduction of gata2 mRNA into PEAK1 knockdown zebrafish restored normal ISV formation and vegfr2 mRNA expression in these animals. Finally, bioinformatics and interrogation of the TCGA RNAseq database revealed significant Pearson’s correlations between PEAK1 and VEGFR2 expression in 17 of 32 different human cancers. Collectively, our findings indicate that PEAK1 regulates developmental and tumor-induced angiogenesis by regulating GATA2-dependent VEGFR2 expression and its downstream signals. Citation Format: Richard L. Klemke. A PEAK1/GATA2 signaling axis controls VEGFR2 expression to mediate angiogenesis [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 1811. doi:10.1158/1538-7445.AM2017-1811
Abstract 1749: Stability of copy-number profiles defines two molecular subtypes during urothelial carcinoma’s evolution
Authors: Bishoy M. Faltas, Davide Prandi, Scott T. Tagawa, David Nanus, Ana M. Molina, Himisha Beltran, Francesca Demichelis, Mark A. Rubin
Journal: Cancer Research (2017)

Abstract Background: Somatic copy-number alterations (SCNAs) are distinct molecular events occurring in muscle-invasive urothelial carcinoma (UC). Defining the biologic role and the timing of SCNAs in UC’s evolution is critical for understanding disease biology and for precision therapy. Methods: To examine whether distinct SCNAs define specific subtypes of UC and characterize the evolutionary dynamics of SCNA acquisition, we conducted whole-exome sequencing (WES) of a discovery cohort of 44 advanced UC tumors and matching germline samples, including 13 pairs of matched primary and metastatic tumors prospectively collected before and after chemotherapy. We queried WES data from 285 UCs from The Cancer Genome Atlas (TCGA) as a validation cohort. We performed a novel in-depth allele-specific copy-number analysis in 2503 cancer genes using the CLONET computational framework, which accounts for tumor ploidy and cellularity to infer the clonal hierarchy of SCNAs. Results: Analysis of SCNAs from tumor pairs within each patient revealed punctuated evolution of SCNAs occurring early in UC’s development followed by minor changes (clonal stasis) throughout the tumor’s lifetime. Two distinct clusters of UCs with strikingly different SCNA profiles in the discovery cohort emerged. Cluster A was defined by diploid copy number background and focal deletions in the 9p21 region (CDKN2A, CDKN2B and MTAP). Cluster B was defined by genome-wide duplications and several enriched amplifications including 1q21.1 (SETDB1 and MLLT11), (P = 0.0002) and 6p22.3 (E2F3), (P = 0.001). TP53 mutations (P = 0.0001) were enriched in the cluster B, consistent with the role of functional p53 as a “guardian of the genome” preventing chromosomal instability. SCNAs clusters A and B were confirmed in the TCGA validation cohort. Cluster A was enriched with tumors belonging to TCGA bladder cancer cluster III (“basal/squamous-like”) (P = 0.02). Conclusions: Using novel allele-specific SCNAs analysis, we define two distinct clusters of UC presenting a framework for understanding this aspect of UC’s biology. In contrast to somatic mutations, SCNAs are clonally static during each tumor’s evolution. This data has important implications for precision medicine for UC. Citation Format: Bishoy M. Faltas, Davide Prandi, Scott T. Tagawa, David Nanus, Ana M. Molina, Himisha Beltran, Francesca Demichelis, Mark A. Rubin. Stability of copy-number profiles defines two molecular subtypes during urothelial carcinoma’s evolution [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 1749. doi:10.1158/1538-7445.AM2017-1749
Abstract 745: Interleukin-13 conjugated quantum dots to identify glioma initiating cells and exosomes
Authors: Achuthamangalam B. Madhankumar, Oliver Mrowczynski, Brad Zacharia, Michael Glantz, Lichong Xu, Becky Webb, Christopher Siedlecki, Akiva Mintz, James R. Connor
Journal: Cancer Research (2017)

Abstract High grade brain tumors like glioblastoma multiforme (GBM) and certain other brain metastatic cancers possess high tumor invasive and infiltrating properties making them harder to detect. Identification of cancer stem cells and exosomes secreted by them in the biofluids like cerebrospinal fluid (CSF) will be an ideal way of detecting the presence of residual cancer after therapy. In the current approach, a ligand conjugated quantum dot (QD) was utilized to specifically label the cancer stem cells and exosomes to identify the presence of IL13Rα2 a tumor invasive marker. Human glioma initiating cells were cultured in adherent form and were exposed to interleukin-13 conjugated quantum dots (IL13QD), which binds the glioma initiating cells expressing IL13Rα2 receptor. Similarly the exosomes isolated from cancer stem cell condition media and CSF was briefly incubated with IL13QD, before analyzing their complexing pattern. Exosomes that were isolated from glioma stem cells and patients CSF were demonstrated to express IL13Rα2 receptor. Fluorescent microscopy, transmission electron microscopy and flow cytometry were performed on the exosomes after complexing with IL13QD. IL13QD was demonstrated to specifically bind glioma stem cells both in the monolayer and spheroid culture. The binding affinity of the exosomes to the quantum dots were quantitatively and qualitatively confirmed by atomic force microscopy (AFM). The morphology and size of exosomes before and after complexing with exosomes were confirmed by electron microscopy and AFM. The density plot from the flow cytometry experiments with IL13QD-exosomes complex indicates a possibility to identify the tumor associated exosomes. Our experiment infers that tumor targeted quantum dots can selectively bind with glioma stem cells and extracellular vesicles (exosomes) that are secreted by cancer cells. This binding profile could be utilized to identify the expression of certain tumor promoting receptors and antigens on the surface of exosomes present in the CSF and cancer stem cells from the glioma patients. Experiments are in progress to identify the tumor initiating cells in an orthotopic mouse glioma tumor model after intravenous administration of wild type IL13 and certain high affinity mutated IL13 conjugated quantum dots, by non-invasive way. Citation Format: Achuthamangalam B. Madhankumar, Oliver Mrowczynski, Brad Zacharia, Michael Glantz, Lichong Xu, Becky Webb, Christopher Siedlecki, Akiva Mintz, James R. Connor. Interleukin-13 conjugated quantum dots to identify glioma initiating cells and exosomes [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 745. doi:10.1158/1538-7445.AM2017-745
Abstract 1448: Unraveling the oncogenic pathway of serrated polyposis syndrome driven by RNF43 germline mutation
Authors: Helen Hoi Ning Yan, Jeffrey C W Lai, Siu Lun Ho, Anthony K W Chan, Wai Yin Tsui, Annie S Y Chan, Siu Tsan Yuen, Suet Yi Leung
Journal: Cancer Research (2017)

Abstract Serrated polyps can arise in a sporadic or familial polyposis setting and predispose to colorectal cancer (CRC). Recently, we have identified RNF43 germline mutation in a family with Serrated Polyposis Syndrome (Yan et al, GUT 2016). The presence of second somatic hit in all serrated polyps examined from members of this family further confirmed the pathogenicity of RNF43 germline mutation. In an attempt to further delineate the global genomic alterations in these serrated polyps, so as to understand the RNF43 driven serrated neoplasia pathway for the development of colorectal cancer, we performed whole exome sequencing (WES) on two sessile serrated adenomas (SSAs) resected from an RNF43 germline mutation carrier, together with the paired blood DNA. Consistent with the results from our previous Sanger sequencing study, WES detected complete inactivation of RNF43 through a 2nd hit somatic mutation, c.461 C&amp;gt;T P154L, or loss of heterozygosity (LOH) in the two SSAs, respectively. We also identified 51 and 58 somatic mutations in the two SSAs, respectively. BRAFV600E mutation was the only shared mutation between the two polyps. Interestingly, each of the SSAs carried a truncating mutation in a histone-methyltransferase gene, either PRDM9 or SETD1B, respectively. Other truncating or deleterious mutations included chromatin modifiers (CHD2, CHD4, TSPYL2) or other genes with methyltransferase activity (TRMT2B, METTL12, METTL14, ECE2). In addition, we found few instances of chromosomal aberration or LOH, apart from a region of LOH at chromosome 17 encompassing RNF43 in one of the SSAs. Overall, we have revealed the genomic landscape of two sessile serrated adenomas resected from a germline RNF43 mutation carrier. The results confirmed somatic RNF43 2nd hit and BRAFV600E mutation as the key events, along with putative roles for histone methyltransferase, as well as other chromatin modifiers. These findings highlight the potentially important role of an altered chromatin in the oncogenic pathway of serrated neoplasia. Citation Format: Helen Hoi Ning Yan, Jeffrey C W Lai, Siu Lun Ho, Anthony K W Chan, Wai Yin Tsui, Annie S Y Chan, Siu Tsan Yuen, Suet Yi Leung. Unraveling the oncogenic pathway of serrated polyposis syndrome driven by RNF43 germline mutation [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 1448. doi:10.1158/1538-7445.AM2017-1448
Abstract 5883: CHD1 as regulator of cell adhesion in Ets fusion negative prostate cancer
Authors: Aparna Kareddula, Whitney Petrosky, Irina Tereshchenko, Daniel Medina, Hana Aviv, Eric Singer, Robert S. DiPaola, Kim M. Hirshfield
Journal: Cancer Research (2017)

Abstract Prostate cancer (PCa) develops into lethal disease in about 10% of men diagnosed with this malignancy. Common genomic changes are seen in PCa such as alterations in CDKN1B, RB1, TP53, PTEN, NKX3-1, MYC and androgen receptor. Oncogenic fusions involving the Ets family are seen in 50-70% PCa patients, the most common of which is TMPRSS2-ERG. TMPRSS2-ERG influences cell migration, particularly when PTEN is co-deleted or PIK3CA activating mutations are present. However, in the absence of ERG fusions, molecular drivers of the PCa phenotype are less clear but include alterations in SPOP (6-15% of PCa), SPINK1 (10%), MAP3K7 (18-38%) and CHD1 (15-27%). CHD1 (Chromo-domain Helicase DNA Binding Protein-1) is a chromatin remodeling factor with many roles including homologous recombination mediated DNA repair of double strand breaks and maintenance of genomic stability and therefore it is hypothesized to cause the predominant intrachromosomal rearrangements observed in Ets fusion negative tumors. This study was undertaken to evaluate the cellular effects that follow CHD1 deletion that could aid PCa initiation and progression. CHD1 was knocked out in the non tumorigenic, HPV16 immortalised prostate epithelial cell line, RWPE-1, using CRISPR/Cas9. Compared to parental RWPE-1 and non target cells (NT2), the CHD1 KO cells had a smaller and rounder morphology and were less adherent to tissue culture plates. To study expression of extracellular matrix and adhesion molecules, RT profiler assay was performed using RWPE-1 parental and CHD1 KO cells. CHD1 KO cells showed a decrease in the expression of SPARC, MMP2, ITGA2, ITGA5, ITGA6, FN1, LAMB3, collagen, tenascin and vitronectin as compared to parentals and NT2. Reduction in extracellular matrix and adhesion molecules and altered morphology of CHD1 KO cells as compared to parentals and NT2 cells suggest that loss of CHD1 reduces cell-cell and cell-matrix adhesion. These results suggest that in the absence of PTEN loss in Ets negative tumors, deletion of CHD1 gene could change cell adhesion dynamics ascribing a new role for CHD1 in the development and progression of PCa. Citation Format: Aparna Kareddula, Whitney Petrosky, Irina Tereshchenko, Daniel Medina, Hana Aviv, Eric Singer, Robert S. DiPaola, Kim M. Hirshfield. CHD1 as regulator of cell adhesion in Ets fusion negative 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 5883. doi:10.1158/1538-7445.AM2017-5883
Abstract 295: CASC-578, a novel Chk1 inhibitor, is active as a single agent in solid tumors and displays synergistic anti-tumor activity in combination with Wee1 inhibition
Authors: Alex Vo, Janelle Taylor, Robert Rosler, Julia Piasecki, Dina Leviten, Teresa Sierra, Ashley Dozier, Kevin Klucher, Bob Boyle, Rich Boyce, Scott Peterson
Journal: Cancer Research (2017)

Abstract Background: Checkpoint kinase 1 (Chk1) is a serine/threonine protein kinase that regulates cell division in response to genotoxic stress by arresting cell cycle progression in the S &amp; G2 phases. Pharmacological inhibition of Chk1 is proposed to target tumor cells with increased DNA replication stress, resulting in the uncoupling of DNA replication checkpoint function and the induction of DNA damage and cell death. These properties make Chk1 inhibition a novel therapeutic approach as a single agent in cancers with high replication stress that is driven by oncogenic signaling and loss of parallel DNA damage response pathway function. Methods and Results: This report highlights the activity of the orally bioavailable, selective small molecule Chk1 inhibitor, CASC-578, in solid tumor derived cell lines. CASC-578 is a sub-nanomolar enzymatic inhibitor of Chk1 with limited off-target activity against a panel of protein kinases. When evaluated in a large cell line panel in vitro, CASC-578 demonstrated a broad potency range as a single agent in solid tumor derived cells lines, with IC50s ranging from 30 nM to greater than 50 μM. Several solid tumor types demonstrated enriched sensitivity to CASC-578 in vitro, including gastric, non-small cell lung and ovarian cancers. Treatment of sensitive cell lines with CASC-578 resulted in the induction of DNA damage, as measured by phosphorylated histone H2AX, and the induction of cell death. CASC-578 was active as a single agent in SK-MES-1 and NCI-H727 NSCLC tumor xenograft models in vivo with minimal effects on body weight in treated mice. In addition to the potent single agent activity of CASC-578, combination with the Wee1 inhibitor AZD-1775 was highly synergistic in vitro in multiple solid tumor cell lines and the combination was more efficacious than either agent alone in NSCLC tumor xenograft models. These data support the advancement of CASC-578 into clinical development as a potential therapeutic agent for the treatment of solid tumor diseases. Experiments are ongoing to identify biomarkers associated with sensitivity to CASC-578 as a single agent in solid tumor cell lines to prospectively identify tumor genotypes that are more responsive to the drug. Citation Format: Alex Vo, Janelle Taylor, Robert Rosler, Julia Piasecki, Dina Leviten, Teresa Sierra, Ashley Dozier, Kevin Klucher, Bob Boyle, Rich Boyce, Scott Peterson. CASC-578, a novel Chk1 inhibitor, is active as a single agent in solid tumors and displays synergistic anti-tumor activity in combination with Wee1 inhibition [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 295. doi:10.1158/1538-7445.AM2017-295
Evaluation of nurse practitioner-led survivorship care.
Authors: Mary S. McCabe, Annelies H. Boekhout, Bridgette Thom, Stacie Corcoran, Roberto Adsuar, Kevin C. Oeffinger
Journal: Journal of Clinical Oncology (2016)

10081 Background: As the number of cancer survivors grows, new models of survivorship care are being implemented internationally, but there is limited evaluation of them to date. This retrospective review assesses the concordance of care provided to adult-onset cancer survivors in nurse practitioner (NP)-led clinics with Institute of Medicine (IOM) guidelines for comprehensive survivorship care. Methods: Records from three survivorship clinics were reviewed to determine frequency of surveillance for recurrence (SR), screening for second cancers, symptom management (physical, psychological), health promotion education (alcohol, tobacco, cholesterol, bone density screenings; discussions on diet, exercise), and care coordination (provision of care plan). Visit length and payor mix were also assessed. Data were characterized using descriptive statistics. Results: From 4Q 2011 - 3Q 2013, 9052 unique visits occurred within the three clinics; 210 breast, 208 prostate, and 204 colorectal visits were randomly selected from these visits for review. All breast patients underwent SR, and 99% received screenings for new primary cancers. Frequency of discussion of designated health promotion activities ranged from 83-100%; 91% of visits discussed physical symptoms, and 93% discussed psychological symptoms. In prostate, 100% of patients underwent SR; 97% were screened for new primaries. Health promotion frequency ranged from 70-97%, depending on activity, and 89% of visits discussed physical/psychological symptoms. In colorectal, all patients underwent a colonoscopy for SR; 97% had a CEA test. Of female colorectal patients, 97% had a mammogram, 96% had a Pap smear; 83% of male patients had a PSA test. Health promotion activities ranged from 69-100%, and 93-97% of visits discussed symptoms. Provision of care plans varied substantially among clinics, due in part to staffing and clinical systems issues: 36% prostate, 70% breast, and 92% colorectal. Conclusions: These findings suggest the success of NP-led clinics in providing quality survivorship care in accordance with IOM standards. While IOM guidelines are not considered a final authority, they provide normative standards. This assessment is an important step in evaluating survivorship outcomes.