tbuckley/cabot-search huggingface dataset:
Epigenetic and Genetic Contributions to Adaptation in Chlamydomonas
Authors: Ilkka Kronholm, Andrew Bassett, David Baulcombe, Sinéad Collins
Journal: Molecular Biology and Evolution (2017)

Epigenetic modifications, such as DNA methylation or histone modifications, can be transmitted between cellular or organismal generations. However, there are no experiments measuring their role in adaptation, so here we use experimental evolution to investigate how epigenetic variation can contribute to adaptation. We manipulated DNA methylation and histone acetylation in the unicellular green alga Chlamydomonas reinhardtii both genetically and chemically to change the amount of epigenetic variation generated or transmitted in adapting populations in three different environments (salt stress, phosphate starvation, and high CO2) for two hundred asexual generations. We find that reducing the amount of epigenetic variation available to populations can reduce adaptation in environments where it otherwise happens. From genomic and epigenomic sequences from a subset of the populations, we see changes in methylation patterns between the evolved populations over-represented in some functional categories of genes, which is consistent with some of these differences being adaptive. Based on whole genome sequencing of evolved clones, the majority of DNA methylation changes do not appear to be linked to cis-acting genetic mutations. Our results show that transgenerational epigenetic effects play a role in adaptive evolution, and suggest that the relationship between changes in methylation patterns and differences in evolutionary outcomes, at least for quantitative traits such as cell division rates, is complex.
STMC-01. OLIGODENDROCYTE PRECURSOR CELL HYPERCELLULARITY IN A MOUSE MODEL OF NEUROFIBROMATOSIS TYPE (NF1) RESEMBLES PRENEOPLASTIC LESIONS
Authors: James Lennon, Preethi Raghavan, David Gutmann, Michelle Monje
Journal: Neuro-Oncology (2017)

Oligodendrocyte precursor cells (OPC) represent the largest population of proliferative cells in the postnatal brain and are involved in white matter remodeling throughout life. However, this proliferative capacity renders OPCs susceptible to transformation. Accordingly, OPCs are thought to be the cell-oforigin for a range of glioma types, including diffuse intrinsic pontine glioma (DIPG), glioblastomas and anaplastic oligodendroglioma. Elucidating the mechanisms by which OPCs transition from healthy to neoplastic is a critical step towards understanding the basic biology of these tumors and ultimately developing effective treatments. In a mouse hemizygous for the tumor suppressor gene Nf1, we identified regions of brain exhibiting increased OPC density. These hyperdense regions appear around postnatal day 35 and worsen as the mouse ages. The OPCs within these regions appear to have normal proliferation rates but loss of the mechanism that maintains a tiled arrangement of single OPC territories throughout the normal brain. The hyperdense appearance of these discrete areas of OPC hypercellularity suggests that they could be preneoplastic lesions. Further characterization of these lesions demonstrates that this phenotype is specific to OPCs, as neither astrocytes nor microglia exhibit alterations in cell density. To evaluate whether the formation of these lesions is intrinsic to OPCs, we utilized an inducible OPC-specific Cre driver (PDGFRα::CreER) to remove one or both Nf1 alleles from OPCs. At four weeks following tamoxifen administration, Nf1fl/fl; PDGFRα::CreER mice have a greater than 2.5-fold increase in OPC density diffusely relative to Nf1+/fl; PDGFRα::CreER and control mice. This suggests that homozygous loss of Nf1 is necessary to alter OPC density. The hypercellular lesions evident in the Nf1 hemizygous mice may arise from OPCs with somatic loss of the remaining Nf1 allele. Ongoing work focuses on intracellular signaling within these presumptively preneoplastic OPCs in order to understand how they differ from healthy and from malignant OPCs.
Histologically defined intratumoral sequencing uncovers evolutionary cues into conserved molecular events driving gliomagenesis
Authors: Antony Prabhu, Pravin Kesarwani, Shiva Kant, Stewart F Graham, Prakash Chinnaiyan
Journal: Neuro-Oncology (2017)

Glioblastoma represents an archetypal example of a heterogeneous malignancy. To understand the diverse molecular consequences of this complex tumor ecology, we analyzed RNA-seq data generated from commonly identified intratumoral structures in glioblastoma enriched using laser capture microdissection. Raw gene-level values of fragments per kilobase of transcript per million reads mapped and the associated clinical data were acquired from the publicly available Ivy Glioblastoma Atlas Project database and analyzed using MetaboAnalyst (v3.0). The database includes gene expression data generated from multiple structural features commonly identified in glioblastoma enriched by laser capture microdissection. We uncovered a relationship between subtype heterogeneity in glioblastoma and its unique tumor microenvironment, with infiltrating cells harboring a proneural signature while the mesenchymal subtype was enriched in perinecrotic regions. When evaluating the tumors' transcriptional profiles in the context of their derived structural regions, there was a relatively small amount of intertumoral heterogeneity in glioblastoma, with individual regions from different tumors clustering tightly together. Analyzing the transcriptional profiles in the context of evolutionary progression identified unique cellular programs associated with specific phases of gliomagenesis. Mediators of cell signaling and cell cycle progression appear to be critical events driving proliferation in the tumor core, while in addition to a multiplex strategy for promoting angiogenesis and/or an immune-tolerant environment, transformation to perinecrotic zones involved global metabolic alterations. These findings suggest that intratumoral heterogeneity in glioblastoma is a conserved, predictable consequence to its complex microenvironment, and combinatorial approaches designed to target these unequivocally present tumor biomes may lead to therapeutic gains.
The Clinical Impact of Minimal Bone Marrow Involvement on the Outcome of Patients with Follicular Lymphoma
Authors: Daisuke Kato, Satoshi Yoshioka, Tomohiro Yabushita, Yoshimitsu Shimomura, Yuichiro Ono, Nobuhiro Hiramoto, Noboru Yonetani, Akiko Matsushita, Hisako Hashimoto, Takayuki Ishikawa
Journal: Blood (2016)
LGG-17. IMPACT OF STROKE AND STROKE RECURRENCE ON LATE MORTALITY AS WELL AS PSYCHOLOGICAL AND SOCIOECONOMIC OUTCOMES IN CHILDHOOD CANCER SURVIVORS
Authors: Sabine Mueller, Yan Chen, Yutaka Yasui, Heather Fullerton, Rebecca Howell, Kevin Oeffinger, Leslie Robison, Gregory Armstrong, Kevin Krull
Journal: Neuro-Oncology (2017)

BACKGROUND: Survivors of childhood cancer treated with cranial radiation therapy (CRT) are at high risk for stroke and stroke recurrence. However, the impact of stroke on psychological and socioeconomic outcomes and late mortality is not known. METHODS: Using the Childhood Cancer Survivor Study cohort, mortality rates (IR) per 100 person-years and 95% confidence intervals (CI) were calculated across three time periods: (1) prior to stroke (stroke free); (2) after first stroke but before recurrent stroke (post stroke); and (3) post recurrent stroke. Associations between stroke and psychological (neurocognitive function, emotional distress, health-related quality of life) and socioeconomic outcomes (education, income, employment, marital status, and independent living) were assessed using multivariable logistic regression adjusted for sex, age at diagnosis, and maximum CRT dose to calculate odds ratios (OR). RESULTS: Among 14,311 5+ year survivors (median age at survey 34.2 years, range 5.6–58.0; median time from diagnosis 26.2 years, range 5.0–38.0) 222 had a stroke ≥ 5years from diagnosis (single n=169; recurrent n=53). Based on 2,021 deaths, the all-cause late mortality rate increased from 0.67 (CI 0.64–0.70) in the stroke-free time period to 3.5 (CI 2.1–6.0) post recurrent stroke. Among 7,205 survivors with longitudinal follow-up, those with history of stroke were: more likely to live with a caregiver (single stroke OR 2.2 (CI 1.4–3.7); recurrent stroke OR 5.1 (CI 1.6–16.0)); limited physical function (single stroke OR 3.0 (CI 1.8–5.1); recurrent stroke OR 10.4 (CI 3.6–30.4)); and increased body pain (single stroke OR 2.0 (CI 1.2–3.4); recurrent stroke OR 3.1, CI 1.1–8.8)). Risk was increased for memory impairment, OR 3.4 (CI 1.1–10.2) and depression OR 4.8 (CI 1.7–13.7) after recurrent stroke. Stroke and stroke recurrence contribute to late mortality and negatively impacts longterm outcome in pediatric cancer survivors. Improved understanding of the pathogenesis of post-CRT stroke is needed to improve stroke prevention strategies.
Pandemic H1N1 influenza: predicting the course of a pandemic and assessing the efficacy of the planned vaccination programme in the United States
Authors: S Towers, Z Feng
Journal: Eurosurveillance (2009)

We use data on confirmed cases of pandemic influenza A(H1N1), disseminated by the United States Centers for Disease Control and Prevention(US CDC), to fit the parameters of a seasonally forced Susceptible, Infective, Recovered (SIR) model. We use the resulting model to predict the course of the H1N1 influenza pandemic in autumn 2009, and we assess the efficacy of the planned CDC H1N1 vaccination campaign. The model predicts that there will be a significant wave in autumn, with 63% of the population being infected, and that this wave will peak so early that the planned CDC vaccination campaign will likely not have a large effect on the total number of people ultimately infected by the pandemic H1N1 influenza virus.
Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis
Authors: Luanne M. Metz, David K.B. Li, Anthony L. Traboulsee, Pierre Duquette, Misha Eliasziw, Graziela Cerchiaro, Jamie Greenfield, Andrew Riddehough, Michael Yeung, Marcelo Kremenchutzky, Galina Vorobeychik, Mark S. Freedman, Virender Bhan, Gregg Blevins, James J. Marriott, Francois Grand’Maison, Liesly Lee, Manon Thibault, Michael D. Hill, V. Wee Yong
Journal: New England Journal of Medicine (2017)

On the basis of encouraging preliminary results, we conducted a randomized, controlled trial to determine whether minocycline reduces the risk of conversion from a first demyelinating event (also known as a clinically isolated syndrome) to multiple sclerosis. During the period from January 2009 through July 2013, we randomly assigned participants who had had their first demyelinating symptoms within the previous 180 days to receive either 100 mg of minocycline, administered orally twice daily, or placebo. Administration of minocycline or placebo was continued until a diagnosis of multiple sclerosis was established or until 24 months after randomization, whichever came first. The primary outcome was conversion to multiple sclerosis (diagnosed on the basis of the 2005 McDonald criteria) within 6 months after randomization. Secondary outcomes included conversion to multiple sclerosis within 24 months after randomization and changes on magnetic resonance imaging (MRI) at 6 months and 24 months (change in lesion volume on T2-weighted MRI, cumulative number of new lesions enhanced on T1-weighted MRI ["enhancing lesions"], and cumulative combined number of unique lesions [new enhancing lesions on T1-weighted MRI plus new and newly enlarged lesions on T2-weighted MRI]). A total of 142 eligible participants underwent randomization at 12 Canadian multiple sclerosis clinics; 72 participants were assigned to the minocycline group and 70 to the placebo group. The mean age of the participants was 35.8 years, and 68.3% were women. The unadjusted risk of conversion to multiple sclerosis within 6 months after randomization was 61.0% in the placebo group and 33.4% in the minocycline group, a difference of 27.6 percentage points (95% confidence interval [CI], 11.4 to 43.9; P=0.001). After adjustment for the number of enhancing lesions at baseline, the difference in the risk of conversion to multiple sclerosis within 6 months after randomization was 18.5 percentage points (95% CI, 3.7 to 33.3; P=0.01); the unadjusted risk difference was not significant at the 24-month secondary outcome time point (P=0.06). All secondary MRI outcomes favored minocycline over placebo at 6 months but not at 24 months. Trial withdrawals and adverse events of rash, dizziness, and dental discoloration were more frequent among participants who received minocycline than among those who received placebo. The risk of conversion from a clinically isolated syndrome to multiple sclerosis was significantly lower with minocycline than with placebo over 6 months but not over 24 months. (Funded by the Multiple Sclerosis Society of Canada; ClinicalTrials.gov number, NCT00666887 .).
Allogeneic bone marrow–derived mesenchymal stromal cells for hepatitis B virus–related acute‐on‐chronic liver failure: A randomized controlled trial
Authors: Bing‐liang Lin, Jun‐feng Chen, Wei‐hong Qiu, Ke‐wei Wang, Dong‐ying Xie, Xiao‐yong Chen, Qiu‐li Liu, Liang Peng, Jian‐guo Li, Yong‐yu Mei, Wei‐zhen Weng, Yan‐wen Peng, Hui‐juan Cao, Jun‐qiang Xie, Shi‐bin Xie, Andy Peng Xiang, Zhi‐liang Gao
Journal: Hepatology (2017)

Mortality from hepatitis B virus (HBV)–related acute‐on‐chronic liver failure (ACLF) is high due to limited treatment options. Preclinical and clinical investigations have proved that treatment with mesenchymal stromal cells (MSCs) is beneficial for recovery from liver injury. We hypothesized that the outcome of HBV‐related ACLF would be improved by MSC treatment. From 2010 to 2013, 110 patients with HBV‐related ACLF were enrolled in this open‐label, nonblinded randomized controlled study. The control group (n = 54) was treated with standard medical therapy (SMT) only. The experimental group (n = 56) was infused weekly for 4 weeks with 1.0 to 10 × 10 5 cells/kg allogeneic bone marrow–derived MSCs and then followed for 24 weeks. The cumulated survival rate of the MSC group was 73.2% (95% confidence interval 61.6%‐84.8%) versus 55.6% (95% confidence interval 42.3%‐68.9%) for the SMT group ( P = 0.03). There were no infusion‐related side effects, but fever was more frequent in MSC compared to SMT patients during weeks 5‐24 of follow‐up. No carcinoma occurred in any trial patient in either group. Compared with the control group, allogeneic bone marrow–derived MSC treatment markedly improved clinical laboratory measurements, including serum total bilirubin and Model for End‐Stage Liver Disease scores. The incidence of severe infection in the MSC group was much lower than that in the SMT group (16.1% versus 33.3%, P = 0.04). Mortality from multiple organ failure and severe infection was higher in the SMT group than in the MSC group (37.0% versus 17.9%, P = 0.02). Conclusion : Peripheral infusion of allogeneic bone marrow–derived MSCs is safe and convenient for patients with HBV‐related ACLF and significantly increases the 24‐week survival rate by improving liver function and decreasing the incidence of severe infections. (H epatology 2017;66:209–219).
HGG-09. NOVEL EPIGENETIC TARGETS IN PEDIATRIC HIGH-GRADE GLIOMA
Authors: Dennis S. Metselaar, Michaël H. Meel, Piotr Waranecki, Marcel de Winter, Kenn Zwaan, Dannis G. van Vuurden, Gertjan L. Kaspers, Esther Hulleman
Journal: Neuro-Oncology (2017)

Pediatric high-grade gliomas (HGGs) are the leading cause of cancer related death during childhood. Recent insights revealed that the epigenetic landscape of HGGs in children shows a distinct pattern from their adult counterparts, as has been shown with pediatric HGG associated H3K27M and H3G34V/R histone modifications. These findings highlight the importance of tailored therapeutic strategies in pediatric HGG. Our research group recently showed that pediatric diffuse midline gliomas are prone to epigenetic targeting via histone deacetylase inhibitors (HDACi). However, single epigenetic targeting therapies lack the effectiveness needed for clinical treatment. Therefore, we hypothesized that the effect might be dampened by rescue mechanisms. In this project we firstly aim to identify epigenetic drugs as potential candidates for pediatric HGG treatment. Secondly, we aim to combine the identified epigenetic drugs with a selection of relevant conventional chemotherapeutics to increase their effectiveness. 15 human pediatric HGG cell lines were cultured both as adherent monolayers and neurospheres. Subsequently, all cultures were treated with over 150 epigenetic drugs. All drugs were tested in absence and presence of conventional fractionated irradiation. Potential drug candidates were selected based on cell growth and viability parameters. The respective treated cells were subjected to total mRNA sequencing in order to identify drug-induced rescue mechanisms. We will give an overview of the targets that have thus far been identified while highlighting their underlying mechanisms and potential as anti-cancer targets in pediatric HGG.
Update in Allergy and Immunology
Authors: Mark T. O'Hollaren
Journal: Annals of Internal Medicine (2000)

Updates from the Annual Session1 February 2000Update in Allergy and ImmunologyMark T. O'Hollaren, MDMark T. O'Hollaren, MDFrom Allergy Clinic, Portland, Oregon.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-132-3-200002010-00008 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail As might be expected, asthma—both its development and its treatment—heads the list of topics for this Update. Other important areas explored here are effective treatment of rhinitis, proper use of allergen immunotherapy, administration of epinephrine for treatment of anaphylaxis, and the proper duration of immunotherapy for prevention of anaphylactic reactions to insect stings.AsthmaThe cause and treatment of asthma continue to be the foremost topics in the field of allergy and immunology. Indoor allergens, such as those produced by dust mites, cockroaches, and cats, are emerging as very important factors in the genesis and maintenance of asthma symptoms. Control ... Author, Article, and Disclosure InformationAffiliations: From Allergy Clinic, Portland, Oregon.Corresponding Author: Mark T. O'Hollaren, MD, Allergy Clinic, 511 SW 10th Avenue, Suite 1301, Portland, OR 97205. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited ByObesity and immune function relationshipsBasic Bibliographies 1 February 2000Volume 132, Issue 3Page: 219-226KeywordsAllergensAllergy and immunologyAllergy immunotherapyAnaphylaxisAsthmaChildrenDustEpinephrineSkin testsVenoms Issue Published: 1 February 2000 CopyrightCopyright © 2000 by American College of Physicians. All Rights Reserved.PDF DownloadLoading ...
Risk of subsequent malignant neoplasms in long-term retinoblastoma survivors following chemotherapy and radiotherapy.
Authors: Jeannette R Wong, Lindsay M. Morton, Margaret A. Tucker, David H. Abramson, Johanna Seddon, Joshua Sampson, Ruth Kleinerman
Journal: Journal of Clinical Oncology (2014)

10079 Background: Hereditary retinoblastoma (Rb) survivors have increased risk for developing subsequent malignant neoplasms (SMN). Previous studies report elevated SMN risks related to radiotherapy (RT), but less is known about chemotherapy-related risks. Patients and Methods: In a long-term follow-up study of 906 five-year hereditary Rb survivors diagnosed 1914-1996 and followed through 2009, risks were quantified using cumulative incidence analyses and compared by type of Rb treatment using hazard ratios (HRs) and 95% confidence intervals (CIs) derived from multivariate Cox proportional hazards regression models. Results: Nearly 90% of Rb survivors were treated with RT and almost 40% received alkylating-agent (AA)-containing chemotherapy. Overall SMN risk was elevated among survivors receiving AA+RT compared to RT (without chemotherapy; HR 1.27, 95%CI 0.99-1.63). AA-related risks were significantly increased for subsequent bone (HR 1.30, 95%CI 1.03-2.49) and leiomyosarcoma (HR 2.67, 95%CI 1.22-5.85), but not melanoma (HR=0.74, 95%CI 0.36-1.55). Leiomyosarcoma risk was higher for survivors who received AAs at <1 year of age (HR 5.17, 95%CI 1.76-15.17) versus ≥1 (HR 1.75, 95%CI 0.68-4.51). Development of leiomyosarcoma was significantly more common among survivors who were treated with AA+RT versus RT (8.7% versus 6.3% at age 50 years, p=0.02). Conclusions: This first comprehensive quantification of SMN risk after chemotherapy and RT among hereditary Rb survivors demonstrates the contribution of AAs to SMN risk. This effect was driven by Rb survivors who were treated with triethylene melamine (64%). Although no longer prescribed, our findings warrant further follow-up to investigate potential SMN risks associated with current chemotherapies used for Rb.
Phosphatase-stable peptidomimetic prodrug inhibitors of signal transducer and activator of transcription 3
Authors: Pijus Mandal, Zhiyong Ren, Inbal Hallevi, Warren Liao, Xiaomin Chen, Zeev Estrov, John McMurray
Journal: Cancer Research (2008)

1306  Signal transducer and activator of transcription 3 (Stat3) transmits signals from IL-6 family cytokines, EGF, Src, etc., is constitutively activated in head and neck, breast, prostate, and other cancers, and is a target for cancer drug design. To develop small molecule inhibitors of Stat3, we have targeted the Stat3 SH2 domain with phosphopeptide-based inhibitors. Molecular modeling of a lead peptide, Ac-pTyr-Leu-Pro-Gln-NHBn, docked to the Stat3 SH2 domain [1] suggested additional modifications that would enhance binding affinity between the inhibitor and the protein. A series of peptidomimetics incorporating these modifications showed 2- to 3-fold increases in binding affinity with IC50 values ranging from 35 - 120 nM in fluorescence polarization assays. Several of these inhibitors were converted to phosphatase-stable, cell-permeable prodrugs by replacing the phosphate with the phosphonodifluoromethyl group and capping the phosphonate with pivaloyloxymethyl (POM) groups. One such compound, PM-252F, when added to MDA MB-468 and BT-20 breast cancer cells completely inhibited constitutive Stat3 phosphorylation at 100 nM and inhibited cell growth with an IC50 of 1-2 μM. PM-252F also inhibited proliferation of primary CLL cells by inducing apoptosis. Thus, we have successfully converted our lead phosphopeptide to a phosphatase-stable and cell-permeable small molecule inhibitor of Stat3.  [1] Biopolymers, 2007, in press