tbuckley/cabot-search huggingface dataset:
Ultra-deep bisulfite sequencing analysis of DNA methylation patterns in multiple gene promoters by massively parallel pyrosequencing
Authors: Kristen Taylor, Robin Kramer, Wade Davis, Dong Xu, Charles Caldwell, Huidong Shi
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

2863 

Bisulfite genomic sequencing is currently considered the gold standard for DNA methylation analysis, but it is very low throughput, laborious and bias can occur during sub-cloning of bisulfite PCR products. Therefore, we investigated the use of massively parallel pyrosequencing technology for directly sequencing bisulfite PCR products. 122 (3 PCR amplification failures) bisulfite PCR amplicons were derived from 25 gene promoters in 5 groups of cells: 1. Normal lymphocytes; 2. ALL; 3. CLL; 4. FL; and 5. MCL. For each sample group, we pooled DNA samples isolated from 10 individuals with the same diagnosis and bisulfite-treated each pooled DNA sample. For each gene promoter, a group of specific 4 nucleotide tag was added to the 5’ end of each PCR primer pair so that the amplicons of the 5 groups could be computationally separated after sequencing. Individual amplicons were generated by PCR from each of the 5 groups for each of the 25 gene promoters. Each amplicon was purified, quantified and pooled together at equal molar ratios. The pooled 122 amplicons were sequenced on the GS20 sequencer from 454 Life Sciences. A total of 294,631 sequences were obtained in a single sequencing run, which included both forward and reverse strands. The average read length was 100bp (ranging from 35 bp to 300bp). We used a dynamic-programming alignment method to map each sequence to the in silico bisulfite-converted amplicon sequence. Among the total sequences, 288,358 were mapped to unique amplicons. Based on the quality of the alignment, 207,011 sequences with a sequence identity > 90% were used for computing methylation levels. The percentage of methylation at each CpG site within each amplicon was calculated based on the number of sequences containing a methylated CpG versus the total number of sequences obtained. Overall, the methylation of the 25 genes analyzed is consistent with our previous results obtained in the same group of samples by other independent methods. However, the new 454 sequencing result reveals great detail about the quantitative methylation at each single methyl-cytosine and the methylation patterns in each amplicon. Using the conventional bisulfite sequencing, only 6 to 8 clones are usually sequenced compared to hundreds and thousands of sequences obtained from the 454 sequencing for each sample. We observed significant differential methylation between normal and tumor samples. The percentage of analyzed CpG sites methylated at or above 20% is 10 times higher in the tumor samples compared to normal control lymphocyte samples (45.64% vs 4.25%). This new generation of methylome sequencing will revolutionize the current analytical methods of DNA methylation, provide digital profiles of aberrant DNA methylation for individual human cancers and offer a robust method for epigenetic classification of tumor subtypes.
Tory plan to double migrant worker surcharge will worsen NHS staffing crisis, says BMA
Authors: Matthew Limb
Journal: BMJ (2017)

The Conservative government’s pledge to double the charge that organisations pay to employ workers from outside the European Economic Area will exacerbate the NHS staffing crisis and “take around £7bn a year from the NHS frontline,” the BMA has said.

The Conservative Party’s manifesto promises that by the end of the next parliament the immigration skills charge, which was introduced in April and currently stands at £1000 (€1165; $1300) per year of a tier 2 visa (for immigrants working in skilled areas), would rise to £2000.

The BMA said that the government had ignored warnings that the immigration skills charge would worsen the NHS staffing crisis. Mark Porter, its chair of council, said, “As overseas staff can only be employed if recruitment from the UK and EU has been unsuccessful, it is completely unacceptable for the …
Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer Aβ Peptides
Authors: Laibaik Park, Ken Uekawa, Lidia Garcia-Bonilla, Kenzo Koizumi, Michelle Murphy, Rose Pistik, Linda Younkin, Steven Younkin, Ping Zhou, George Carlson, Josef Anrather, Costantino Iadecola
Journal: Circulation Research (2017)

Increasing evidence indicates that alterations of the cerebral microcirculation may play a role in Alzheimer disease, the leading cause of late-life dementia. The amyloid-β peptide (Aβ), a key pathogenic factor in Alzheimer disease, induces profound alterations in neurovascular regulation through the innate immunity receptor CD36 (cluster of differentiation 36), which, in turn, activates a Nox2-containing NADPH oxidase, leading to cerebrovascular oxidative stress. Brain perivascular macrophages (PVM) located in the perivascular space, a major site of brain Aβ collection and clearance, are juxtaposed to the wall of intracerebral resistance vessels and are a powerful source of reactive oxygen species.We tested the hypothesis that PVM are the main source of reactive oxygen species responsible for the cerebrovascular actions of Aβ and that CD36 and Nox2 in PVM are the molecular substrates of the effect.Selective depletion of PVM using intracerebroventricular injection of clodronate abrogates the reactive oxygen species production and cerebrovascular dysfunction induced by Aβ applied directly to the cerebral cortex, administered intravascularly, or overproduced in the brain of transgenic mice expressing mutated forms of the amyloid precursor protein (Tg2576 mice). In addition, using bone marrow chimeras, we demonstrate that PVM are the cells expressing CD36 and Nox2 responsible for the dysfunction. Thus, deletion of CD36 or Nox2 from PVM abrogates the deleterious vascular effects of Aβ, whereas wild-type PVM reconstitute the vascular dysfunction in CD36-null mice.The data identify PVM as a previously unrecognized effector of the damaging neurovascular actions of Aβ and unveil a new mechanism by which brain-resident innate immune cells and their receptors may contribute to the pathobiology of Alzheimer disease.
Abstract #3528: Nrf2-driven adaptive defense response to inflammation caused by dextran sulfate sodium in mouse colonic mucosa
Authors: Jeong-Sang Lee, Ji-Youn Cho, Ki-Baik Hahm, Hye-Kyung Na, Young-Joon Surh
Journal: Cancer Research (2009)

A wide array of phase II detoxifying or antioxidant enzymes constitute a fundamental cellular defense system against oxidative and electrophilic stresses. The major cellular cytoprotective enzymes include heme oxygenase-1 (HO-1), NADPH:quinone oxidoreductase (NQO-1), and glutamate cysteine ligase (GCL). Inappropriately elevated expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) has been implicated in inflammation and tumor promotion. However, the interactions/cross-talks between cellular signaling pathways responsible for antioxidant gene induction and those mediating proinflammatory protein expression are not fully understood. In an attempt to investigate the possible role of antioxidant enzymes in protecting against inflammatory damage, we utilized the dextran sulfate sodium (DSS)-induced colitis mouse model. Treatment of male ICR mice with 2.5% of DSS in drinking water for 7 days caused inflammatory injury in colonic mucosa which was accompanied by significant induction of COX-2 and iNOS. The DNA binding activities of NF-\#954;B and AP-1, two major transcription factors known to upregulate proinflammatory gene expression, were elevated following DSS administration. Degradation of I\#954;B\#945;, the NF-\#954;B repressor, was also more prominent in the DSS-treated mouse colon. In addition, DSS treatment accelerated phosphorylation of c-Jun N-terminal kinase (JNK) and Akt. When the COX-2 knock out (cox-2 -/-) mice were treated with DSS, the colonic damage was less severe than that observed in wild-type mice. The promoter regions of HO-1, NQO-1, and GCL harbor the specific sequence named antioxidant response elements (ARE) or electrophile reponse elements (EpRE) to which the transcription factor Nrf2 binds preferentially. The transcriptional activity of Nrf2, as measured by use of ARE-hPAP (human placental alkaline phosphatase) transgenic reporter mice, was gradually increased in the colon as a consequence of DSS treatment. In the cox-2 -/- mice, DSS-induced HO-1 expression was significantly decreased compared with that observed in cox-2 +/+ animals. The nrf2-/- mice were more prone to DSS-induced inflammatory damage compared with nrf2+/+ mice. Taken together, these results suggest that Nrf2-ARE driven induction of HO-1 expression confers adaptive survival response to DSS-induced inflammation in mouse colon.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3528.
ACCF/ACR/AHA/ASE/ASNC/HRS/NASCI/RSNA/SAIP/SCAI/SCCT/SCMR 2008 Health Policy Statement on Structured Reporting in Cardiovascular Imaging
Authors: Pamela S. Douglas, Robert C. Hendel, Jennifer E. Cummings, John M. Dent, John McB. Hodgson, Udo Hoffmann, Robert J. Horn, W. Gregory Hundley, Charles E. Kahn, Gerard R. Martin, Frederick A. Masoudi, Eric D. Peterson, Geoffrey L. Rosenthal, Harry Solomon, Arthur E. Stillman, Shawn D. Teague, James D. Thomas, Peter L. Tilkemeier, Wm. Guy Weigold
Journal: Circulation (2008)
Targeting latency-associated peptide promotes antitumor immunity
Authors: Galina Gabriely, Andre P. da Cunha, Rafael M. Rezende, Brendan Kenyon, Asaf Madi, Tyler Vandeventer, Nathaniel Skillin, Stephen Rubino, Lucien Garo, Maria A. Mazzola, Panagiota Kolypetri, Amanda J. Lanser, Thais Moreira, Ana Maria C. Faria, Hans Lassmann, Vijay Kuchroo, Gopal Murugaiyan, Howard L. Weiner
Journal: Science Immunology (2017)

Anti-LAP antibody induces antitumor immunity by affecting both adaptive and innate immune mechanisms.
BRAF mutation in circulating DNA of melanoma patients at baseline and intertumor heterogeneity.
Authors: Marc G. Denis, Anne-Chantal Knol, Audrey Vallee, Amir Khammari, Helene Caillon, Melanie Saint-Jean, Lucie Peuvrel, Anabelle Brocard, Gaelle Quereux, Brigitte Dreno
Journal: Journal of Clinical Oncology (2014)

9017 Background: Determination of the BRAF mutation status is a requirement for treatment selection of metastatic melanoma patients. However, the inter and intra-tumor genetic heterogeneity for BRAF status has been described supporting the need for testing multiple sites for the same patient. Circulating DNA is considered a promising non-invasive tool for cancer monitoring. The objective of our work was to determine the potential of plasma DNA to detect BRAF mutations, particularly in patients presenting discordant BRAF status from different tumor sites. Methods: Plasma DNA was extracted using the iPrep PureLink Virus Kit on an iPrep purification system (Invitrogen). BRAF mutations were detected using the Therascreen BRAF RGQ kit (Qiagen). Results: Ninety-nine patients were included, and plasma was collected at baseline. Nine stage III melanoma patients presenting a mutant BRAF (6 V600E, 2 V600K and 1 V600D) were tested and for 4 of them we detected the corresponding mutation (including the V600D and both V600K) in circulating DNA (sensitivity 44.4 %). Similarly, 20 stage IV patients were tested (17 V600E, 2 V600K and 1 V600R). The corresponding mutation (including the V600R and both V600K) was detected in 15 of these patients (sensitivity 75.0%). Interestingly, 4 stage IV patients included in our series presented discordant BRAF mutation status on different sites (1 patient with a WT primary tumor (PT) and a V600E lymph node (LN) metastasis; 1 patient with a V600E PT and WT LN metastasis; 2 patients with a V600E PT, V600E LN and WT liver metastasis). We were able to detect the expected BRAF mutation in circulating DNA for all these patients. Conclusions: The sensitivity of our procedure, based on approved kits, suggests a high interest for use in clinical practice, even for non-V600E mutations. Plasma DNA might be less sensitive to heterogeneity between tumor samples, and therefore might represent an interesting alternative source of DNA to detect BRAF mutations in clinical setting.
The Influence of Maternally Derived Antibody and Infant Age at Vaccination on Infant Vaccine Responses
Authors: Merryn Voysey, Dominic F. Kelly, Thomas R. Fanshawe, Manish Sadarangani, Katherine L. O’Brien, Rafael Perera, Andrew J. Pollard
Journal: JAMA Pediatrics (2017)

The design of infant immunization schedules requires an understanding of the factors that determine the immune response to each vaccine antigen.Deidentified individual participant data from GlaxoSmithKline clinical trials were obtained through Clinical Study Data Request. The data were requested on January 2, 2015, and final data were received on April 11, 2016.Immunogenicity trials of licensed or unlicensed vaccines administered to infants were included if antibody concentrations in infants were measured prior to the first dose of vaccine.The database was examined; studies that appeared to have appropriate data were reviewed.Antigen-specific antibody concentration measured 1 month after priming vaccine doses, before booster vaccination, and 1 month after booster vaccine doses.A total of 7630 infants from 32 studies in 17 countries were included. Mean (SD) age at baseline was 9.0 (2.3) weeks; 3906 (51.2%) were boys. Preexisting maternal antibody inhibited infant antibody responses to priming doses for 20 of 21 antigens. The largest effects were observed for inactivated polio vaccine, where 2-fold higher maternal antibody concentrations resulted in 20% to 28% lower postvaccination antibody concentration (geometric mean ratios [GMRs], type 1: 0.80; 95% CI, 0.78-0.83; type 2: 0.72; 95% CI, 0.69-0.74; type 3: 0.78; 95% CI, 0.75-0.82). For acellular pertussis antigens, 2-fold higher maternal antibody was associated with 11% lower postvaccination antibody for pertussis toxoid (GMR, 0.89; 95% CI, 0.87-0.90) and filamentous hemagglutinin (GMR, 0.89; 95% CI, 0.88-0.90) and 22% lower pertactin antibody (GMR, 0.78; 95% CI, 0.77-0.80). For tetanus and diphtheria, these estimates were 13% (GMR, 0.87; 95% CI, 0.86-0.88) and 24% (GMR, 0.76; 95% CI, 0.74-0.77), respectively. The influence of maternal antibody was still evident in reduced responses to booster doses of acellular pertussis, inactivated polio, and diphtheria vaccines at 12 to 24 months of age. Children who were older when first immunized had higher antibody responses to priming doses for 18 of 21 antigens, after adjusting for the effect of maternal antibody concentrations. The largest effect was seen for polyribosylribitol phosphate antibody, where responses were 71% higher per month (GMR, 1.71; 95% CI, 1.52-1.92).Maternal antibody concentrations and infant age at first vaccination both influence infant vaccine responses. These effects are seen for almost all vaccines contained in global immunization programs and influence immune response for some vaccines even at the age of 24 months. These data highlight the potential for maternal immunization strategies to influence established infant programs.
Left Ventricular Concentric Remodeling Is Associated With Decreased Global and Regional Systolic Function
Authors: Boaz D. Rosen, Thor Edvardsen, Shenghan Lai, Ernesto Castillo, Li Pan, Michael Jerosch-Herold, Shantanu Sinha, Richard Kronmal, Donna Arnett, John R. Crouse, Susan R. Heckbert, David A. Bluemke, Joao A.C. Lima
Journal: Circulation (2005)

Background— The transition from compensatory concentric remodeling to myocardial failure is not completely understood in humans. To investigate determinants of incipient myocardial dysfunction, we examined the association between concentric remodeling and regional LV function in asymptomatic participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Methods and Results— Myocardial tagged MRI was performed. Regional myocardial function expressed as peak systolic midwall circumferential strain (Ecc) was analyzed in 441 consecutive studies by HARP (Harmonic Phase) tool. Peak Ecc was correlated with the extent of concentric remodeling determined by the ratio of left ventricular mass to end-diastolic volume (M/V ratio). In men, a gradual decline in peak global Ecc was seen with increasing M/V ratio (test for trend, P &lt;0.001). Among women, however, Ecc tended to be lower only in the fifth compared with the first quintile of M/V ratio ( P =0.1). The association of lower Ecc with increasing M/V ratio was regionally heterogeneous but was particularly prominent in the LAD region in men (test for trend, P &lt;0.001) and in women (test for trend, P =0.02). In the right coronary and left circumflex artery territories, these associations were less marked in both genders. Conclusions— In this cross-sectional study of asymptomatic individuals, concentric left ventricular remodeling was related to decreased regional systolic function. The reduction in regional function, which was more pronounced in the left anterior descending coronary artery territory, may reflect the local transition from compensatory remodeling to myocardial dysfunction.
Abstract 100: Delta Opioid Receptor Blockade Abolishes Exercise-Induced Cardioprotection Against Ischemia-Reperfusion Injury In Vivo
Authors: Juliana P Borges, Marina Tristao, Eduardo V Tibiriçá, Marcos A Lessa
Journal: Circulation Research (2013)

Introduction: Recent studies showed that exercise enhances myocardial tolerance to ischemia-reperfusion (I-R) injury via an opioid receptor-dependent mechanism. However, the specific subtype of opioid receptor involved in this response remains to be determined. Methods: Male Wistar rats were first divided into 2 groups: exercised and control. The exercised group underwent 4 consecutive days of treadmill training (60 min at 70% of maximal oxygen consumption). The exercised group was then divided into 4 subgroups: exercised (Exe; n = 10); exercised + kappa receptor antagonist (Exe + K; n=4); exercised + delta receptor antagonist (Exe + D; n=4); exercised + mu receptor antagonist (Exe + M; n=4). Control group was also divided into 2 groups: control (Ctr; n = 10) and control sham (Sham; n = 10). To induce I-R injury, anesthetized animals were submitted to a left thoracotomy and a 30 min interventricular coronary occlusion followed by 60 min of reperfusion. The hemodynamic parameters were recorded and infarct size was post-mortem determined by double staining using TTC/Evans blue and expressed as a percentage of the area at risk. Results: As shown in the figure, Sham group showed no infarct, Exe group showed a significant reduction in the infarcted area (27.6%) when compared to Ctr group (42.0%). The pretreatment with mu and kappa receptor antagonist did not alter the cardioprotective effect of exercise. However, the pretreatment with delta receptor antagonist prevented the exercise-induced cardioprotection. Conclusions: Endogenous opioid system is involved in cardioprotection conferred by acute exercise, and delta receptor subtype seems to play an important role in this response.
Abstract 18976: Protein Kinase G is a Redox Sensor That Controls Autophagic Flux by Phosphorylating Tuberin
Authors: Mark J Ranek, Kristen M Kokkonen, Ronald J Holewinski, Dong I Lee, Taishi Nakamura, Guangshuo Zhu, Masayuki Sasaki, Jennifer E Van Eyk, David A Kass
Journal: Circulation (2016)

Pathological cardiac hypertrophy requires an imbalance that favors protein synthesis over its degradation, the latter being prominently controlled by autophagy. Both changes are induced by mechanis...
Review: In COPD, injectable polyvalent pneumococcal vaccines reduce risk for community-acquired pneumonia
Authors: Matthew B. Stanbrook
Journal: Annals of Internal Medicine (2017)

Source Citation Walters JA, Tang JN, Poole P, Wood-Baker R. Pneumococcal vaccines for preventing pneumonia in chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2017;1:CD001390. 28116747
Reversal of Autoimmune Toxicity and Loss of Tumor Response by Interleukin-17 Blockade
Authors: Khashayar Esfahani, Wilson H Miller
Journal: New England Journal of Medicine (2017)

In a patient with colon cancer and a history of autoimmunity, skin and gastrointestinal toxicity developed after the receipt of pembrolizumab. Interleukin-17 blockade reversed the autoimmunity but led to tumor progression.
A Triumph for the Agency for Healthcare Research and Quality Safety Program for Long-term Care
Authors: Elizabeth G. Turnipseed, C. Seth Landefeld
Journal: JAMA Internal Medicine (2017)

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