tbuckley/cabot-search huggingface dataset:
High Satellite Repeat Turnover in Great Apes Studied with Short- and Long-Read Technologies
Authors: Monika Cechova, Robert S Harris, Marta Tomaszkiewicz, Barbara Arbeithuber, Francesca Chiaromonte, Kateryna D Makova
Journal: Molecular Biology and Evolution (2019)

Satellite repeats are a structural component of centromeres and telomeres, and in some instances, their divergence is known to drive speciation. Due to their highly repetitive nature, satellite sequences have been understudied and underrepresented in genome assemblies. To investigate their turnover in great apes, we studied satellite repeats of unit sizes up to 50 bp in human, chimpanzee, bonobo, gorilla, and Sumatran and Bornean orangutans, using unassembled short and long sequencing reads. The density of satellite repeats, as identified from accurate short reads (Illumina), varied greatly among great ape genomes. These were dominated by a handful of abundant repeated motifs, frequently shared among species, which formed two groups: 1) the (AATGG)n repeat (critical for heat shock response) and its derivatives; and 2) subtelomeric 32-mers involved in telomeric metabolism. Using the densities of abundant repeats, individuals could be classified into species. However, clustering did not reproduce the accepted species phylogeny, suggesting rapid repeat evolution. Several abundant repeats were enriched in males versus females; using Y chromosome assemblies or Fluorescent In Situ Hybridization, we validated their location on the Y. Finally, applying a novel computational tool, we identified many satellite repeats completely embedded within long Oxford Nanopore and Pacific Biosciences reads. Such repeats were up to 59 kb in length and consisted of perfect repeats interspersed with other similar sequences. Our results based on sequencing reads generated with three different technologies provide the first detailed characterization of great ape satellite repeats, and open new avenues for exploring their functions.
Abstract 1787: Selective activation of a PI3K catalytic isoform by G protein-coupled receptors in glioblastoma
Authors: Abigail R. Winn, Zhi Sheng
Journal: Cancer Research (2019)

Abstract Objective: To determine how PI3K catalytic isoforms become dysregulated in glioblastoma. Background: Recurrence in glioblastoma (GBM) is common and even more resistant to treatment than initial GBM. The Sheng Lab has previously identified that PIK3CB expression levels, but not other PI3K subtypes, are higher in recurrent GBM and are associated with GBM recurrence in newly diagnosed individuals. PI3KCB encodes for PI3K catalytic subunit p110β, and PI3K/AKT pathway activation is a well-known promoter of cell survival. Understanding mechanisms of PIK3CB activation in GBM may identify new therapeutic targets and improve GBM survival. Current knowledge of PI3K isoform activity in GBM is insufficient and contradictory. Given previous studies, it was hypothesized that G-Coupled Protein Receptor (GPCR) promoters preferentially activate PI3K/AKT in PIK3CBhigh GBM cells. Further, that knockdown of PIK3CB, but not other PI3K isoforms, inhibits PI3K/AKT reactivation in PIK3CBhigh cell lines. Design/Methods: U87MG cells, an established p110βhigh GBM cell line, were starved overnight in serum free media, and then treated with growth factors, promoters or inhibitors of several previously hypothesized pathways. Cell lysates were collected and PI3K/AKT pathway activity was measured with immunoblotting. The ratio of pAKT/AKT/ACTB quantified PI3K/AKT pathway activity. Results: Overnight serum starvation depleted pAKT, and incubation with 1% FBS restored pAKT signaling in a time dependent manner. Neither EGF nor FGF-2 activated PI3K/AKT signaling. Gefitinib, an EGFR inhibitor, failed to inhibit reactivation when cells were co-treated with 1% FBS. However, GPCR stimulation by Lysophosphatidic acid (LPA) increased pAKT/AKT ratios in a dose dependent manner. More significantly, Gallein, a GPCR inhibitor, suppressed PI3K/AKT signaling when cells were co-treated with 1% FBS. Selective PI3K inhibitors showed little PI3K/AKT reactivation at multiple doses. Conclusions: These results suggest that GPCR signaling is responsible for PI3K/AKT pathway activation in p110βhigh cells. Citation Format: Abigail R. Winn, Zhi Sheng. Selective activation of a PI3K catalytic isoform by G protein-coupled receptors in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1787.
Long-Term Particulate Matter Exposure and Onset of Depression in Middle-Aged Men and Women
Authors: Zhenyu Zhang, Di Zhao, Yun Soo Hong, Yoosoo Chang, Seungho Ryu, Danbee Kang, Joao Monteiro, Ho Cheol Shin, Eliseo Guallar, Juhee Cho
Journal: Environmental Health Perspectives (2019)

Background: Long-term exposure to particulate matter (PM) air pollution is associated with all-cause mortality and adverse cognitive outcomes, but the association with developing depression remains inconsistent. Objective: Our goal was to evaluate the prospective association between PM air pollution and developing depression assessed using the Center for Epidemiological Studies Depression (CES-D) scale. Methods: Subjects were drawn from a prospective cohort study of 123,045 men and women free of depressive symptoms at baseline who attended regular screening exams in Seoul and Suwon, South Korea, from 2011 to 2015. Exposure to PM with an aerodynamic diameter of ≤10 and≤2.5μm (PM10 and PM2.5, respectively) was estimated using a land-use regression model based on each subject's residential postal code. Incident depression was defined as a CES-D score ≥16 during follow-up. As a sensitivity analyses, we defined incident depression using self-reports of doctor's diagnoses or use of antidepressant medications during follow-up. Results: The mean baseline 12-month concentrations of PM10 and PM2.5 were 50.6 (4.5) and 24.3 (1.3) μg/m3, respectively. The hazard ratios (HRs) and 95% confidence intervals (CIs) for developing depression associated with a 10-μg/m3 increase in 12- and 60-month PM10 exposure were 1.11 (95% CI: 1.06, 1.16) and 1.06 (95% CI: 1.01, 1.11), respectively. The corresponding HRs for 12-month PM2.5 exposure was 0.96 (95% CI: 0.64, 1.43). Similar results were obtained when incident depression was identified using self-reports of doctor's diagnoses or the use of antidepressant medications. Conclusion: In this large cohort study, we found a positive association between long-term exposure to outdoor PM10 air pollution and the developing depression. We did not find an association for outdoor PM2.5 air pollution; however, we had a much shorter follow-up for subjects' exposure to PM2.5. https://doi.org/10.1289/EHP4094
Lymphoma Chemotherapy: Hungry Macrophages Strike the Final Blow
Authors: Florent Duval, Michele De Palma
Journal: Cancer Discovery (2019)

Abstract Summary: Macrophages modulate tumor response to chemotherapy; in this issue, Lossos and colleagues show that high-dose alkylating agents instigate a synthetic lethal program in lymphoma cells that is independent of DNA damage and involves recruitment and priming of macrophages for antibody-mediated tumor phagocytosis. These findings implicate chemotherapy-elicited macrophages as critical effectors of lymphoma clearance during biological therapy. See related article by Lossos et al., p. 944.
Neuroimaging Biomarkers for Alzheimer’s Disease
Authors: Freddie Márquez, Michael A. Yassa
Journal: Molecular Neurodegeneration (2019)

Currently, over five million Americans suffer with Alzheimer's disease (AD). In the absence of a cure, this number could increase to 13.8 million by 2050. A critical goal of biomedical research is to establish indicators of AD during the preclinical stage (i.e. biomarkers) allowing for early diagnosis and intervention. Numerous advances have been made in developing biomarkers for AD using neuroimaging approaches. These approaches offer tremendous versatility in terms of targeting distinct age-related and pathophysiological mechanisms such as structural decline (e.g. volumetry, cortical thinning), functional decline (e.g. fMRI activity, network correlations), connectivity decline (e.g. diffusion anisotropy), and pathological aggregates (e.g. amyloid and tau PET). In this review, we survey the state of the literature on neuroimaging approaches to developing novel biomarkers for the amnestic form of AD, with an emphasis on combining approaches into multimodal biomarkers. We also discuss emerging methods including imaging epigenetics, neuroinflammation, and synaptic integrity using PET tracers. Finally, we review the complementary information that neuroimaging biomarkers provide, which highlights the potential utility of composite biomarkers as suitable outcome measures for proof-of-concept clinical trials with experimental therapeutics.
Abstract 15395: Estimating Coronary Heart Disease Morbidity and Mortality From Heterozygous Familial Hypercholesterolemia in the United States
Authors: Michael M Mendelson, Radley C Sheldrick, Angie Rodday, Laurel Leslie, Joshua Cohen, John B Wong, Sarah D de Ferranti
Journal: Circulation (2015)

Introduction: With an estimated prevalence of 1 in 299 in the United States based on clinical criteria in NHANES (Circulation.2014;130:A19656), heterozygous Familial Hypercholesterolemia (FH) is widely suspected to be underdiagnosed and undertreated in the U.S. despite increased risk for premature coronary heart disease (CHD). The population burden of FH if undiagnosed and untreated in the US population is unknown. Methods: Using an FH prevalence of 1 in 250 (0.4%) to account for genotypic FH (in addition to our prior 1 in 299 estimate) and U.S. population census data and assuming 90% undetected and untreated, we developed, calibrated and validated a Markov model of the natural history of FH in the U.S. population, including fatal and nonfatal CHD. A sensitivity analysis considers alternative prevalence and detection rates. Results: For the base case 0.4% FH prevalence with 90% of individuals undiagnosed, the model projected that undetected FH led to over 44,000 CHD deaths and over 132,000 years of lost life for a ten-year period. The model also predicted that 37% (range 23-62%) would develop premature (age &lt; 60 years) CHD and 59% (range 43-77%) would develop fatal or nonfatal CHD. Missed FH diagnosis account for 2.4% of premature CHD deaths and 0.6% of all CHD deaths in the U.S. The figure provides estimates of the proportion of premature CHD mortality attributable to undetected FH for varying estimates of prevalence and detection prior to CHD event. Conclusions: Undetected FH, a disease that can be safely and effectively treated, significantly contributes to overall CHD mortality in the U.S., particularly premature CHD. Strategies to attain AHA 2020 prevention goals would be enhanced by incorporating efforts to determine and implement optimal national population strategies to detect and treat FH.
TLR9 signalling in HCV-associated atypical memory B cells triggers Th1 and rheumatoid factor autoantibody responses
Authors: Cloé Comarmond, Valérie Lorin, Cindy Marques, Anna Maciejewski-Duval, Nizar Joher, Cyril Planchais, Maxime Touzot, Lucie Biard, Thierry Hieu, Valentin Quiniou, Anne-Claire Desbois, Michelle Rosenzwajg, David Klatzmann, Patrice Cacoub, Hugo Mouquet, David Saadoun
Journal: Journal of Hepatology (2019)
Abstract 946: Early signs of activity of Tedopi OSE2101, a multiple neoepitope vaccine, in a phase 3 trial in advanced lung cancer patients after failure to previous immune checkpoint inhibitors ATALANTE-1
Authors: Santiago Viteri, François-Roger Vanel, Werner Hilgers, Jordi Remon, Guillermo Viteri-Ramirez, Elisabeth Quoix
Journal: Cancer Research (2019)

Abstract Introduction: Tedopi is a neoepitope vaccine restricted to HLA-A2 positive patients targeting five tumor-associated antigens frequently expressed in lung cancer cells. Potential enhanced efficacy of cancer vaccines after ICI treatment remains unexploited and its biological basis is poorly understood. The integrity of the antigen presentation pathway is crucial in vaccine activity and genetic alterations such as beta-2-microglobulin inactivating mutation may explain lack of efficacy. Tedopi is currently being tested in the phase III ATALANTE-1 trial compared with chemotherapy in advanced NSCLC patients (pts.) who relapse after ICI. We report early signs of safety and efficacy with Tedopi in the first step of the open-label study. Methods: 18 pts have been enrolled in the experimental arm and received at least one dose of Tedopi. These pts have been assessed every 6 weeks for radiological response according to RECIST 1.1 criteria as well as toxicity according to CTCAE criteria. Tedopi dose was 5 mg injected subcutaneously every 3 weeks for 6 doses, then every 2 months completing 1 year of treatment and thereafter every 3 months until progression or toxicity. Description of three patients with significant clinical benefit with third-line treatment with Tedopi is presented. Results: Patients’ clinical characteristics are reported in table 1. Treatment duration with Tedopi ranges from 4.9 to more than 12 months, including one patient with brain metastases. One patient achieved a partial response and two patients achieved stable disease by RECIST 1.1 criteria. Safety profile was manageable and no patient withdrawn for toxicity. Conclusions: Tedopi after failure to previous ICI therapy as third-line treatment has shown long-term clinical benefit and good safety profile. Baseline genomic molecular profile assessment, as well as, immunophenotype searching evidence of vaccination are ongoing. Citation Format: Santiago Viteri, François-Roger Vanel, Werner Hilgers, Jordi Remon, Guillermo Viteri-Ramirez, Elisabeth Quoix. Early signs of activity of Tedopi OSE2101, a multiple neoepitope vaccine, in a phase 3 trial in advanced lung cancer patients after failure to previous immune checkpoint inhibitors ATALANTE-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 946.
Abstract 1171: Identifying small molecules that specifically inhibit glioma stem cells
Authors: Anthony R. Sloan, Raffaella Spina, Dillon M. Voss, Sophie Laye, Eli E. Bar
Journal: Cancer Research (2019)

Abstract Glioblastomas (GBM) are the most common primary malignant brain tumor in adults and are recognized as one of the deadliest forms of cancer. Despite aggressive therapy consisting of maximal surgical resection followed by concomitant radiation and temozolomide (TMZ) chemotherapy, GBM remains to have a median survival time of ~ 15 months. Glioblastoma stem cells (GSCs) are suggested to play a critical role in the GBM phenotype; GSC have tumor initiation ability, propagation ability, and have been shown to be a driver in promoting GBM resistance to current therapeutic interventions. Due to these poor clinical outcomes and resistance to current treatments, more potent and preferably more specific pharmacological therapies are needed in order to target cellular-molecular pathways to eradicate GSCs and effectively treat GBM. In an effort to identify agents that specifically inhibit GSC growth, we recently conducted a drug screen of over 3,000 small molecules. HSR020913 patient derived neurospheres were treated for 72 hours with library agents at a concentration of 10 µM and cell growth was observed for a period of 5 days. We identified twelve highly potent compounds in the primary screen that inhibited the growth of HSR020913 neurospheres by over 50%. Subsequently, the potency of these compounds was tested on five additional GBM patient derived neurosphere lines (HSR040622, HSR040822, CCF3691, CCF3832, and CCF08-387) at even lower concentrations. We next sought to determine the specificity of these compounds in killing GSCs but not normal cells. To this aim we tested these compounds against immortalized human neural stem cells (v-Myc hNSCs) and normal human astrocytes (NHA). Of the twelve potent compounds identified in the primary screen, three compounds (AGSC9, AGSC11, AGSC12) showed to have negligible to minimal effect, only at higher doses, on normal neural stem cells. The respective half maximal inhibitory concentration (IC50) was determined for all the neurosphere lines utilized. Subsequent studies determined the inhibitory effect of these compounds on clonogenic capacity and enzymatic activity. Future studies are warranted to identify molecular pathways targeted by these compounds and determine their effect on tumor progression and survival in vivo. Citation Format: Anthony R. Sloan, Raffaella Spina, Dillon M. Voss, Sophie Laye, Eli E. Bar. Identifying small molecules that specifically inhibit glioma stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1171.
Minimal important difference of the Chronic Urticaria Quality of Life Questionnaire (CU‐Q2oL)
Authors: Ilaria Baiardini, Salvatore Fasola, Marcus Maurer, Karsten Weller, Giorgio Walter Canonica, Fulvio Braido
Journal: Allergy (2019)

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PAM50 HER2-enriched (HER2E) phenotype as a predictor of early-response to neoadjuvant lapatinib plus trastuzumab in stage I to IIIA HER2-positive breast cancer.
Authors: Maria Vidal, Lorena De La Pena, Mafalda Oliveira, Javier Cortes, Antonio Llombart, Aleix Prat
Journal: Journal of Clinical Oncology (2013)

TPS665 Background: Combinations of two different anti-HER2 therapies without chemotherapy have generated great expectations. However, it is unclear which group of patients benefits the most from this strategy. Within HER2-positive breast cancer, the PAM50 assay identifies a HER2-Enriched HER2-E intrinsic subtype characterized by high activation of the EGFR/HER2 pathway. Trial Design: This non-randomized, open label multi-centre translational research study will evaluate the ability of the HER2-E subtype to predict pathological complete response (pCR) to dual HER2 blockade with lapatinib and trastuzumab for a total of 18 weeks. Patients with hormone receptor (HR)-positive disease will also receive endocrine therapy. Eligibility Criteria: Operable primary Stage I-IIIa HER2+ breast cancer. Specific Aims: The primary objective is to evaluate the ability of the PAM50 assay to predict pCR in the breast at the time of surgery.Secondary objectives are to (1) assess the correlation of HER2-E with pCR in the breast and axilla, (2) assess the correlation of HER2-E with Residual Cancer Burden (RCB) (3) evaluate the gene expression changes from Day 0 to Day 14 and the correlations with Ki67-IHC at Day 14, (4), identify additional gene expression signatures predictive of pCR, and (5) evaluate safety and tolerability. Methods: The statistical plan is based on the assumption that breast pCR rate will be 35.0% for HER2-E tumors and 8.0% for non-HER2E. The study will have a 95% power with a significance level of 5% (two-sided) and an assumed drop-out rate of 15%. Biomarker Analyses: Baseline, 14-day treated and post-treatment (surgical) formalin–fixed, paraffin–embedded tissues will be obtained. The expression of 547 genes will be explored with the nCounter platform. Subtype will be identified using the PAM50 predictor (Parker et al. J Clin Oncol 2009). Ki-67-IHC will also be evaluated on pre-treatment and Day-14 samples. Target Accrual: 150 patients with a maximum of 75 HR-positive patients across Spain and Portugal. Patient enrollment will begin in May 2013.
Abstract 14092: Remnant Cholesterol as a Causal Risk Factor for Ischemic Heart Disease
Authors: Marianne Benn, Anette Varbo, Anne Tybjærg-Hansen, Anders B Jørgensen, Ruth Frikke-Schmidt, Børge G Nordestgaard
Journal: Circulation (2012)

Objective. We tested the hypothesis that elevated nonfasting remnant cholesterol is a causal risk factor for ischemic heart disease independent of reduced HDL cholesterol. Background. Elevated remn...
Clinical Response of Live-Attenuated, <i>Listeria monocytogenes</i> Expressing Mesothelin (CRS-207) with Chemotherapy in Patients with Malignant Pleural Mesothelioma
Authors: Raffit Hassan, Evan Alley, Hedy Kindler, Scott Antonia, Thierry Jahan, Somayeh Honarmand, Nitya Nair, Chan C. Whiting, Amanda Enstrom, Ed Lemmens, Takahiro Tsujikawa, Sushil Kumar, Gina Choe, Anish Thomas, Katherine McDougall, Aimee L. Murphy, Elizabeth Jaffee, Lisa M. Coussens, Dirk G. Brockstedt
Journal: Clinical Cancer Research (2019)

Malignant pleural mesothelioma (MPM) is an aggressive cancer associated with poor prognosis. CRS-207 is a live-attenuated
The Transplant Optimization Program (TOP): Implementing a geriatric assessment (GA)-guided interdisciplinary clinic (IDC) prior to allogeneic hematopoietic cell transplantation (HCT) in older adults.
Authors: Benjamin Avi Derman, Keriann Kordas, Jean Ridgeway, Selina Lai-ming Chow, William Dale, Yung-Hsuan Hsiao, Marc Paloma, Jennifer Pisano, Thomas Rosinski, Michael Russell Bishop, Andrew S. Artz
Journal: Journal of Clinical Oncology (2019)

7045 Background: Limitations found on GA correlate with worse outcomes after HCT, but no data exists on prospectively utilizing GA prior to HCT. We established the TOP IDC in March 2013 to implement a cancer-specific GA and an IDC to risk-stratify HCT candidacy and create an individualized care plan for allograft candidates 60+ yrs. Methods: The IDC consisted of a HCT physician, advanced practice provider, dietician, PT/OT, social worker, ID physician, and a geriatric oncologist to devise a pt specific optimization strategy. We compared consecutive HCT pts ≥ 60 years undergoing GA prior to TOP implementation (pre-TOP) from 2005-2012 (n=75) to TOP pts from 2013-2018 (n=86). Results: 3/89 HCT pts 60+ yrs who did not attend TOP were excluded; all 3 died before 1 year post-HCT. Compared with controls, the TOP group was older (median age 67 vs. 64 yrs, p&lt;0.001) but was similar in HCT-CI ≥ 3 (37% vs. 48%, p=0.2), use of myeloablative regimens (20% vs. 19%, p=0.8), and advanced ASBMT risk disease (46% for both). Relative to the pre-TOP group, TOP pts at baseline had fewer impairments in independent activities of daily living (30% vs. 48%, p=0.02) and fewer frail 4-meter walk tests (7% vs. 31%, p&lt;0.001). Pts undergoing optimization in TOP fared better versus pre-TOP (Table). 1-yr non-relapse mortality (NRM) and 1-yr overall survival (OS) continued to improve including 11% NRM and 89% OS in 2017. Conclusions: A GA-guided interdisciplinary optimization clinic for allograft recipients age 60+ reduced transplant associated morbidity and mortality, with marked improvements in NRM and OS over time. A GA-based IDC can facilitate selection and optimization of older pts considering HCT.[Table: see text]