tbuckley/cabot-search huggingface dataset:
The Association between Ambient Fine Particulate Air Pollution and Lung Cancer Incidence: Results from the AHSMOG-2 Study
Authors: Lida Gharibvand, David Shavlik, Mark Ghamsary, W. Lawrence Beeson, Samuel Soret, Raymond Knutsen, Synnove F. Knutsen
Journal: Environmental Health Perspectives (2016)

There is a positive association between ambient fine particulate matter ≤ 2.5 μm in aerodynamic diameter (PM2.5) and incidence and mortality of lung cancer (LC), but few studies have assessed the relationship between ambient PM2.5 and LC among never smokers.We assessed the association between PM2.5 and risk of LC using the Adventist Health and Smog Study-2 (AHSMOG-2), a cohort of health conscious nonsmokers where 81% have never smoked.A total of 80,285 AHSMOG-2 participants were followed for an average of 7.5 years with respect to incident LC identified through linkage with U.S. state cancer registries. Estimates of ambient air pollution levels at participants' residences were obtained for 2000 and 2001, the years immediately prior to the start of the study.A total of 250 incident LC cases occurred during 598,927 person-years of follow-up. For each 10-μg/m3 increment in PM2.5, adjusted hazard ratio (HR) with 95% confidence interval (CI) for LC incidence was 1.43 (95% CI: 1.11, 1.84) in the two-pollutant multivariable model with ozone. Among those who spent > 1 hr/day outdoors or who had lived 5 or more years at their enrollment address, the HR was 1.68 (95% CI: 1.28, 2.22) and 1.54 (95% CI: 1.17, 2.04), respectively.Increased risk estimates of LC were observed for each 10-μg/m3 increment in ambient PM2.5 concentration. The estimate was higher among those with longer residence at enrollment address and those who spent > 1 hr/day outdoors. Citation: Gharibvand L, Shavlik D, Ghamsary M, Beeson WL, Soret S, Knutsen R, Knutsen SF. 2017. The association between ambient fine particulate air pollution and lung cancer incidence: results from the AHSMOG-2 study. Environ Health Perspect 125:378-384; http://dx.doi.org/10.1289/EHP124.
<i>Yellow Painting (Abstraction)</i>
Authors: Philip Sefton
Journal: JAMA (2016)

“Painting cannot be the only activity of a mature artist,” painter Ad Reinhardt (1913-1967) once commented, and his life as a teacher, art historian, graphic designer, commercial artist, cartoonist, polemicist, art theorist, and social activist is ample testament to his commitment to that idea.
Rituximab Added to CODOX-M/IVAC has No Clear Benefit Compared to CODOX-M/IVAC alone in Adult Patients with Burkitt Lymphoma.
Authors: Barnes A. Barnes, Ann S. LaCasce, Yang Feng, Christiana Toomey, Donna Neuberg, Ephraim P. Hochberg, Jeremy S. Abramson
Journal: Blood (2009)
Abstract 1236: ONC201 sensitivity profiling indicates pronounced sensitivity in lymphoid, prostate, colon and brain tumors
Authors: Rohinton Tarapore, Mathew Garnett, Ultan McDermott, Cyril Benes, Joshua Allen
Journal: Cancer Research (2016)

Abstract ONC201 is a first-in-class small molecule inducer of the integrated stress response that is currently in phase II clinical trials in select advanced cancers and exhibits a benign safety profile and promising early clinical results. The efficacy of this novel agent has been demonstrated in a variety of preclinical advanced cancer models in multiple indications with an exceptional safety profile that has translated well to the clinic. To better characterize the differential sensitivity of tumor cells to ONC201 we performed in vitro efficacy assays in the Genomic of Drug Sensitivity in Cancer collection of cell lines (&amp;gt;1,000 cell lines), in addition to profiling in NCI60 panel. Sensitivity profiling was assessed by cell viability assays using dose responses curves at concentrations up to 20uM and at 72 hours post-treatment. Ranking the sensitivity dataset by tumor type revealed that lymphoma, colon, prostate and brain cancers were highly responsive to ONC201. The strongest predictor of sensitivity to ONC201 was tumor type, with lymphoma being the strong predictor. Within lymphomas, diffuse histiocytic lymphoma was the most sensitive subtype. Mutations that are frequent in lymphoma were not associated with ONC201 sensitivity. Recent mechanistic studies have implicated the ER stress response in the early stage mechanism of ONC201 that triggers its downstream antitumor effects. The mutation-agnostic efficacy that is pronounced in lymphomas, prostate, colon, and brain cancers is in accordance with the recent findings that ONC201 induces the integrated stress response through a novel target to trigger is downstream late apoptotic effects. Cancers of the prostate and brain (glioblastoma multiforme) are among some of the solid tumors that are susceptible to induction of apoptosis via the integrated stress response, as they have relatively high basal activation of this pathway due to ER stress. Confirmatory studies revealed that brain cancer cell lines and ex vivo samples indeed possess pronounced sensitivity with nanomolar GI50s, unlike most other tumor types, which is particularly encouraging given the systemic concentrations observed in the first-in-man study. Together, these studies suggest specific advanced cancer indications, such as non-Hodgkin's lymphoma, multiple myeloma, and glioblastoma as promising lead indications for this novel agent that are being evaluated in phase II clinical trials. Citation Format: Rohinton Tarapore, Mathew Garnett, Ultan McDermott, Cyril Benes, Joshua Allen. ONC201 sensitivity profiling indicates pronounced sensitivity in lymphoid, prostate, colon and brain tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1236.
M011L-deficient oncolytic myxoma virus to induce apoptosis in brain tumor initiating cells and to enhance survival in a novel immunocompetent mouse model of glioblastoma.
Authors: Rajappa Kenchappa, Brienne McKenzie, Alexandra Pisklakova, Grant McFadden, Peter A. J. Forsyth
Journal: Journal of Clinical Oncology (2016)

e13521 Background: Myxoma virus (MYXV) is a promising oncolytic agent, highly effective against immortalized glioma cells but less effective against brain tumor initiating cells (BTICs), which are believed to mediate glioma development/recurrence. MYXV encodes various proteins to attenuate host cell apoptosis, including an anti-apoptotic Bcl-2 homologue known as M011L. Such proteins may limit the ability of MYXV to kill BTICs, which have heightened resistance to apoptosis. We hypothesized that infecting BTICs with an M011L-deficient MYXV construct would overcome BTIC resistance to MYXV. Methods: We used patient-derived BTICs to evaluate the efficacy of M011L knock-out virus (vMyx-M011L-KO) versus wild type MYXV (vMyx-WT) and characterized the mechanism of virally-induced cell death in vitro. To extend our findingsin a novel immunocompetent animal model, we derived, cultured, and characterized a C57Bl/6J murine BTIC (mBTIC0309) from a spontaneous murine glioma and evaluated vMyx-M011L-KO efficacy with and without temozolomide (TMZ) in mBTIC0309-bearing mice. Results: We demonstrated that vMyx-M011L-KO induces apoptosis in BTICs, dramatically increasing sensitivity to the virus. vMyx-WT failed to induce apoptosis, as M011L protein prevented Bax activation and cytochrome c release. In vivo, intracranial implantation of mBTIC0309 generated tumors that closely recapitulated the pathological and molecular profile of human gliomas. Treatment of tumor-bearing mice with vMyx-M011L-KO significantly prolonged survival in immunocompetent but not immunodeficient mouse models, an effect that is significantly enhanced in combination with TMZ. Conclusions: Our data suggest vMyx-M011L-KO is an effective, well-tolerated, pro-apoptotic oncolytic virus, and a strong candidate for clinical translation.
Abstract 1935: A role for microRNAs in the regulation of transcription factor ATF5
Authors: Kari A. Gaither, David X. Liu, Bhanupriya Madarampalli
Journal: Cancer Research (2016)

Abstract ATF5 is a widely expressed transcription factor that modulates survival, proliferation, and differentiation and plays a role in homeostasis and cellular stress response. In unstressed conditions, ATF5 has a short half-life and is rapidly degraded due to post-translational modifications. Conversely, ATF5 is upregulated in cells under cellular stress. Furthermore, we have found that ATF5 is elevated in transformed C6 glioma and MCF7 breast cancer compared to nontransformed cells and is a survival factor for both transformed cell lines. Although it is known that ATF5 mRNA can be stabilized at the 5’ untranslated region (UTR) and protected from degradation via interactions with other proteins, regulation of ATF5 expression is not fully understood. We hypothesize that microRNA (miRNA) play a role in regulating the expression of ATF5 at the 3’ UTR. MiRNAs are endogenous small non-coding RNAs 20-25 nucleotides in length that contribute to regulation of gene expression at the translational level. Herein, we sought to identify the presence of specific miRNA and their levels and ability to downregulate ATF5 during cellular stress and other physiological conditions in vitro. To date, no studies have examined the regulation of ATF5 by miRNA. Binding sites of miRNA are typically found in the UTRs of target mRNAs. We used TargetScan, miRanda, and other in silico modeling programs to identify miRNAs that were predicted to bind to the 3’ UTR of ATF5 and selected miRNAs 129-5p, 433-3p, and 520b as initial candidates for their potential in regulation of ATF5. Here, we have employed multiple strategies to investigate a potential role of miRNAs in the regulation of ATF5. Luciferase reporter assays were used as an initial method of validation for the miRNA candidates. Subsequently, transfections were carried out with precursor microRNA and expression levels of ATF5 were measured under varying physiological conditions via Western blot analysis. Additionally, immunoprecipitations were carried out with ATF5 3’ UTR mRNA and HeLa cell lysate to assess the presence of miRNAs and quantify the amount of specific miRNA bound to the 3’ UTR under varying physiological conditions via qPCR analysis. Preliminary data show that miRNA are bound to the 3’ UTR of ATF5 and that miRNAs 129-5p, 433-3p, and 520b help to regulate the expression of ATF5 under varying stress conditions and at steady state. Better understanding of the regulation of ATF5 could have implications in a broad range of human malignancies, including glioma and potentially several other types of cancer. Citation Format: Kari A. Gaither, David X. Liu, Bhanupriya Madarampalli. A role for microRNAs in the regulation of transcription factor ATF5. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1935.
CDC Grand Rounds: Adolescence — Preparing for Lifelong Health and Wellness
Authors: Stephen Banspach, Stephanie Zaza, Patricia Dittus, Shannon Michael, Claire D. Brindis, Phoebe Thorpe
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Approximately 42 million adolescents aged 10-19 years, representing 13% of the population, resided in the United States in 2014 (1). Adolescence is characterized by rapid and profound physical, intellectual, emotional, and psychological changes (2), as well as development of healthy or risky behaviors that can last a lifetime. Parents have strong influence on their adolescent children's lives, and family-based programs can help parents support healthy adolescent development. Because schools are natural learning environments, implementing and improving school-based policies and programs are strategic ways to reinforce healthy behaviors and educate adolescents about reducing risky behaviors. Health care during adolescence should be tailored to meet the changing developmental needs of the adolescent while providing welcoming, safe, and confidential care. Parents, educators, care providers, public health officials, and communities should collaborate in fostering healthy environments for all adolescents, now and into the future.
Excellent Outcome and Good Tolerability of Long-Term Imatinib in Patients with Chronic Myeloid Leukemia (CML)
Authors: Simone Claudiani, Nikhita Gupta, Ji Soo Baik, Simona Deplano, Renuka Palanicawander, Gareth Gerrard, Alistair G Reid, Richard M Szydlo, Dragana Milojkovic, Letizia Foroni, Jane F. Apperley
Journal: Blood (2015)
Closure of an intestinal perforation with an autologous fat plug in a man with Crohn’s disease
Authors: Yuyong Tan, Dalian Ou, Xuehong Wang, Jie Zhang, Deliang Liu, Jirong Huo
Journal: Endoscopy (2016)

A 44-year-old man presented to our hospital with a 4-year history of recurrent abdominal pain and diarrhea. It had been suspected at his local hospital that he had Crohn's disease, so he came to our hospital for a further assessment. Retrograde double-balloon enteroscopy (DBE) was performed. A perforation overlying a deep ulcer was seen at the lower part of the ileum during withdrawal of the enteroscope ([Fig. 1 a]).
Abstract 1254: Small molecule targeting of the kRAS mid-G-quadruplex for potential pancreatic cancer therapeutics
Authors: Rhianna K. Morgan, Tracy A. Brooks
Journal: Cancer Research (2016)

Abstract Pancreatic cancer is disproportionally lethal (7% of all cancer deaths), as compared to its incidence (3% of cancer incidences) within the United States. One of the most important genetic alterations in pancreatic cancer is within the kRAS oncogene. Over 60% of all pancreatic cancers, and up to 95% of pancreatic ductal adenocarcinomas, harbor mutations in this oncogene. While approaches to therapeutically modulate kRAS activity have not yielded clinical agents, downregulation of expression shows promise in preclinical models. To date, no molecular target has allowed for small molecule mediated downregulation of kRAS expression; however, the promoter region holds promise for a new approach. The kRAS promoter has three distinct guanine-rich regions capable of forming higher order non-B-DNA structures, G-quadruplexes (G4s). In particular the middle (mid) of these three regions forms a stable, inducible, and transcriptionally silencing G4 structures, whereas the more distal (far) region forms no such structure, and the more proximal (near) region has little to no biological function. The structure of this mid-region G4 has been elucidated by electromobility shift assay, DMS footprinting, and circular dichroism (CD). Small molecules capable of stabilizing this structure have been screened from the NCI Diversity Set III by the FRET melt assay, confirmed by CD, and examined for their downregulation of kRAS promoter activity. From the 1600 compounds, the indoloquinolone NSC 317605 is the lead molecule identified. It is particularly interesting as it prefers the mid-, as opposed to the near-, G4 and significantly reduces kRAS promoter activity. This is in contrast to the ellipticine NSC 176327, which favors the near-, over the mid-, G4 and does not decrease kRAS promoter activity. The effect of each compound on cell viability on kRAS transcription is under examination in a panel of pancreatic cancer cells. These works support previous findings that the mid-, and not the near-G4, harbors the potential to transcriptionally downregulate kRAS, and identify a new scaffold for future development. Brooks Lab startup funds, DoD, Rhianna Morgan GSC Grant, University of Mississippi School of Pharmacy Citation Format: Rhianna K. Morgan, Tracy A. Brooks. Small molecule targeting of the kRAS mid-G-quadruplex for potential pancreatic cancer therapeutics. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1254.
Abstract 2360: GP350 containing exosomes as DNA vaccine carriers
Authors: Viswa Teja Colluru, Douglas G. McNeel
Journal: Cancer Research (2016)

Abstract Background: Plasmid DNA vaccination is a safe and economical vaccine modality that has been demonstrated to elicit cellular and humoral immunity in preclinical models and human clinical trials. We have previously shown that enriched mature naive B cells, and not myeloid/DC lineages, are capable of expanding Ag specific CD8 T cells in vivo in mice, and in vitro with human cells. In this study, we sought a means to directly deliver plasmid DNA to B cells as a means to specifically activate this antigen-presenting cell type. Methods: Exosomes were isolated from EBV+ lymphoblastic cell lines (LCL) and from HEK293T cells that had been transfected to express the EBV protein GP350. Plasmid DNA was labeled with a fluorescent peptide nucleic acid (PNA) probe for detection by imaging and conventional cytometry. Exosomes were transfected with fluorescently labeled plasmid DNA and incubated with either human CD21 transgenic mouse splenocytes or human PBMC and assayed for uptake and activation by FACS. Plasmid DNA transfected exosomes were coincubated with human PBMC and evaluated for their ability to expand antigen-specific CD8+ T cells by different methods. Results: EBV LCL and HEK293T derived exosomes were successfully transfected with plasmid DNA as verified by image assisted flow cytometry. Transient transfection of HEK293T cells with plasmids encoding a transgene led to release of exosomes containing the transgene product. EBV LCL and HEK 293T-GP350 derived exosomes increased delivery of plasmid DNA to both human B lymphocytes and transgenic hCD21 mouse B lymphocytes, when compared to naked DNA alone, in an hCD21 dependent fashion. At 24h, plasmid DNA containing B lymphocytes exhibited increased activation and upregulation of CD80/86 costimulatory molecules. Further, human B lymphocytes treated with exosome-plasmid DNA complexes led to antigen mRNA production and expansion of Ag specific CD8 T cells without the need for APC subset enrichment. Studies comparing the immunogenicity of GP350-exosome mediated delivery versus naked DNA delivery are underway in different mouse models. Conclusion: GP350 containing exosomes can successfully increase delivery of plasmid DNA to B lymphocytes even in the presence of other phagocytic cells like macrophages or dendritic cells. This led to detectable antigen production and expansion of cognate Ag specific CD8 T cell expansion without the need for B cell enrichment. Studies examining in vivo immunogenicity of exosomal plasmid DNA delivery are underway, but results to date suggest this approach may be a simple method to boost vaccine efficacy through increased delivery of DNA directly to relevant antigen-presenting B cells. Citation Format: Viswa Teja Colluru, Douglas G. McNeel. GP350 containing exosomes as DNA vaccine carriers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2360.
Image Gallery: Dermoscopy of phthiriasis pubis: a handy and useful tool
Authors: I. Marin‐Cabanas, J.C. Pascual
Journal: British Journal of Dermatology (2016)

Funding sources: no external funding. Conflicts of interest: none to declare. Dear Editor, A 42‐year‐old man presented with a 3‐week history of intense, generalized pruritus. Examination showed multiple 1–2 mm yellowish‐brown dots in the hair of the back (a, circle). Dermoscopy revealed pubic lice (b, c, arrows) and nits (b, stars). Although phthiriasis pubis is a sexually transmitted infestation most commonly found in pubic hair, it can also be attached to coarse hair of the trunk, limbs or eyelashes. Dermoscopy helps to identify pubic lice because of their crab‐like claws and body shape, which distinguishes them from other lice infestations.1 The patient was treated successfully with two applications of topical permethrin 5% cream 1 week apart.
Abstract LB-340: A novel method for estimating somatic mutations cellular prevalence in cancer using whole genome haplotype phasing
Authors: Donatien Chedom-Fotso, Ahmed Ahmed, Christopher Yau
Journal: Cancer Research (2016)

Abstract The process of malignant transformation results in the acquisition of complex chromosomal copy number alterations and somatic mutations. Moreover, cancer exhibits extensive intra-tumor heterogeneity with multiple sub-populations of tumor cells containing both common and private genomic alterations. Within- and between-patient tumor heterogeneity is now seen as one of the major obstacles for precision medicine and the development of effective treatment strategies. Revealing the proportion of cells affected by particular somatic changes is emerging as a key factor for designing targeted therapies, characterizing tumor evolution and understanding chemotherapy-resistance mechanisms. Determining the proportion of cells harboring a particular mutation (the so called cellular prevalence) is a difficult task as it is confounded by several variables. Normal cell contamination, local copy number profile and the temporal relationship between the mutation and the copy number alteration represent some of the key variables. In order to more effectively quantify the cellular prevalence of somatic mutations we developed a novel method, which uses a combination of side, and haplotype phase information obtained from long fragment read sequencing to more accurately compute mutational prevalence. The method utilizes three sources of information: the phasing information, the copy number variation and the allele counts for prevalence estimation using a simple equation in both a linear and a non-linear form. We present theoretical examples of known genomics alterations and show using simulation that our method was able to accurately estimate the cellular prevalence compared to standard methods. We also apply our method to a real data set obtained from dense long fragment read sequencing of a single ovarian cancer and demonstrate the highly accurate estimation of cellular prevalence. Finally we provide an implementation of the method in the statistical software. Citation Format: Donatien Chedom-Fotso, Ahmed Ahmed, Christopher Yau. A novel method for estimating somatic mutations cellular prevalence in cancer using whole genome haplotype phasing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-340.