tbuckley/cabot-search huggingface dataset:
Beneficial Role of Erythrocyte Adenosine A2B Receptor–Mediated AMP-Activated Protein Kinase Activation in High-Altitude Hypoxia
Authors: Hong Liu, Yujin Zhang, Hongyu Wu, Angelo D’Alessandro, Gennady G. Yegutkin, Anren Song, Kaiqi Sun, Jessica Li, Ning-Yuan Cheng, Aji Huang, Yuan Edward Wen, Ting Ting Weng, Fayong Luo, Travis Nemkov, Hong Sun, Rodney E. Kellems, Harry Karmouty-Quintana, Kirk C. Hansen, Bihong Zhao, Andrew W. Subudhi, Sonja Jameson-Van Houten, Colleen G. Julian, Andrew T. Lovering, Holger K. Eltzschig, Michael R. Blackburn, Robert C. Roach, Yang Xia
Journal: Circulation (2016)

Background: High altitude is a challenging condition caused by insufficient oxygen supply. Inability to adjust to hypoxia may lead to pulmonary edema, stroke, cardiovascular dysfunction, and even death. Thus, understanding the molecular basis of adaptation to high altitude may reveal novel therapeutics to counteract the detrimental consequences of hypoxia. Methods: Using high-throughput, unbiased metabolomic profiling, we report that the metabolic pathway responsible for production of erythrocyte 2,3-bisphosphoglycerate (2,3-BPG), a negative allosteric regulator of hemoglobin-O 2 binding affinity, was significantly induced in 21 healthy humans within 2 hours of arrival at 5260 m and further increased after 16 days at 5260 m. Results: This finding led us to discover that plasma adenosine concentrations and soluble CD73 activity rapidly increased at high altitude and were associated with elevated erythrocyte 2,3-BPG levels and O 2 releasing capacity. Mouse genetic studies demonstrated that elevated CD73 contributed to hypoxia-induced adenosine accumulation and that elevated adenosine-mediated erythrocyte A2B adenosine receptor activation was beneficial by inducing 2,3-BPG production and triggering O 2 release to prevent multiple tissue hypoxia, inflammation, and pulmonary vascular leakage. Mechanistically, we demonstrated that erythrocyte AMP-activated protein kinase was activated in humans at high altitude and that AMP-activated protein kinase is a key protein functioning downstream of the A2B adenosine receptor, phosphorylating and activating BPG mutase and thus inducing 2,3-BPG production and O 2 release from erythrocytes. Significantly, preclinical studies demonstrated that activation of AMP-activated protein kinase enhanced BPG mutase activation, 2,3-BPG production, and O 2 release capacity in CD73-deficient mice, in erythrocyte-specific A2B adenosine receptor knockouts, and in wild-type mice and in turn reduced tissue hypoxia and inflammation. Conclusions: Together, human and mouse studies reveal novel mechanisms of hypoxia adaptation and potential therapeutic approaches for counteracting hypoxia-induced tissue damage.
Intratumor Heterogeneity of Homologous Recombination Deficiency in Primary Breast Cancer
Authors: Marie-Kristin von Wahlde, Kirsten M. Timms, Anees Chagpar, Vikram B. Wali, Tingting Jiang, Veerle Bossuyt, Ozlen Saglam, Julia Reid, Alexander Gutin, Chris Neff, Jerry S. Lanchbury, Christos Hatzis, Erin Hofstatter, Lajos Pusztai
Journal: Clinical Cancer Research (2016)

Purpose: The 3-biomarker homologous recombination deficiency (HRD) assay measures the number of telomeric allelic imbalances, loss of heterozygosity, and large-scale state transitions in tumor DNA and combines these metrics into a single score that reflects DNA repair deficiency. The goal of this study is to assess the consistency of these HRD measures in different biopsies from distinct areas of the same cancer.Experimental Design: HRD scores, BRCA mutation status, and BRCA1 promoter methylation were assessed in 99 samples from 33 surgically resected, stage I-III breast cancers; each cancer was biopsied in three distinct areas. Homologous recombination repair (HR) deficiency was defined as either high HRD score (≥42) or tumor BRCA mutation.Results: Eighty-one biopsies from 32 cancers were analyzed. Tumor BRCA status was available for all samples, HRD scores for 70, and BRCA1 methylation values for 76 samples. The BRCA1/2 mutation and promoter methylation status and HR category showed perfect concordance across all biopsies from the same cancer. All tumors with BRCA1/2 mutations or promoter methylation had high HRD scores, as did 17% (4/24) of the BRCA1/2 wild-type and nonmethylated tumors. The HRD scores were also highly consistent between different biopsies from the same tumor with an intraclass correlation coefficient of 0.977, indicating that only 2.3% of the variance is attributed to within-tumor biopsy-to-biopsy variation.Conclusions: These results indicate that within-tumor spatial heterogeneity for HRD metrics and the technical noise in the assay are small and do not influence HRD scores and HR status. Clin Cancer Res; 23(5); 1193-9. ©2016 AACR.
Evaluation of the Global Lung Initiative 2012 Reference Values for Spirometry in African Children
Authors: Michele Arigliani, Mario C. Canciani, Giovanni Mottini, Michele Altomare, Andrea Magnolato, Sofia Vanda Loa Clemente, Leon Tshilolo, Paola Cogo, Philip H. Quanjer
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Despite the high burden of respiratory disease, no spirometry reference values for African children are available.Investigate whether the Global Lung Initiative (GLI-2012) reference values for spirometry are appropriate for children in sub-Saharan Africa and assess the impact of malnutrition on lung function.Anthropometry and spirometry were obtained in children aged 6 to 12 years from urban and semiurban schools in three African countries. Spirometry z-scores were derived using the GLI-2012 prediction equations for African Americans. Thinness (body mass index z-score < -2) was a surrogate for malnutrition. Spirometry outcomes were compared with those of African American children from the third National Health and Nutrition Survey.Spirometry data were analyzed from 1,082 schoolchildren (51% boys) aged 6.0 to 12.8 years in Angola (n = 306), Democratic Republic of the Congo (n = 377), and Madagascar (n = 399). GLI-2012 provided a good fit with mean (SD) z-scores of -0.11 (0.83) for FEV1, -0.08 (0.86) for FVC, and -0.07 (0.83) for FEV1/FVC. Because of low scatter, the fifth centile corresponded to -1.3 z-scores in boys and -1.5 z-scores in girls. Malnourished African children had a normal FEV1/FVC ratio but significant reductions of ∼0.5 z-scores (∼5%) in FEV1 and FVC compared with African American peers from the third National Health and Nutrition Survey. Children in Angola had the lowest, and those in Madagascar had the highest, zFEV1 and zFVC.The results of this study support the use of GLI-2012 reference values for schoolchildren in sub-Saharan Africa. Malnutrition affects body growth, leading to a proportionately smaller FEV1 and FVC without respiratory impairment, as shown by the normal FEV1/FVC ratio.
Comparison of Lung Clearance Index and Magnetic Resonance Imaging for Assessment of Lung Disease in Children with Cystic Fibrosis
Authors: Mirjam Stahl, Mark O. Wielpütz, Simon Y. Graeber, Cornelia Joachim, Olaf Sommerburg, Hans-Ulrich Kauczor, Michael Puderbach, Monika Eichinger, Marcus A. Mall
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Early onset and progression of lung disease in children with cystic fibrosis (CF) indicates that sensitive noninvasive outcome measures are needed for diagnostic monitoring and early intervention clinical trials. The lung clearance index (LCI) and chest magnetic resonance imaging (MRI) were shown to detect early lung disease in CF; however, the relationship between the two measures remains unknown.To correlate the LCI with abnormalities detected by MRI and compare the sensitivity of the two techniques to detect responses to therapy for pulmonary exacerbations in children with CF.LCI determined by age-adapted multiple breath washout techniques and MRI studies were performed in 97 clinically stable children with CF across the pediatric age range (0.2-21.1 yr). Furthermore, LCI (n = 26) or MRI (n = 10) were performed at the time of pulmonary exacerbation and after antibiotic therapy. MRI was evaluated using a dedicated morphofunctional score.The LCI correlated with the global MRI score as well as MRI-defined airway wall abnormalities, mucus plugging, and abnormal lung perfusion in infants and toddlers (P < 0.05 to P < 0.001) and in older children (P < 0.001) with CF. LCI and MRI were sensitive to detect response to antibiotic therapy for pulmonary exacerbations.Our results indicate that LCI and MRI may be useful complementary tools for noninvasive monitoring and as quantitative endpoints in early intervention trials in children with CF. In this context, MRI enables detection of disease heterogeneity, including regional mucus plugging associated with abnormal lung perfusion in early CF lung disease. Clinical trial registered with www.clinicaltrials.gov (NCT 02270476).
No Conflict, No Interest
Authors: Ryan D. Nipp, Beverly Moy
Journal: JAMA Oncology (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
PEG-aspargase and DEP regimen combination therapy for refractory Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis
Authors: Jingshi Wang, Yini Wang, Lin Wu, Jia Zhang, Wenyuan Lai, Zhao Wang
Journal: Journal of Hematology & Oncology (2016)

Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is the most frequent subtype of secondary HLH triggered by infections. Previous studies have shown that ~30 % or more of patients with EBV-HLH do not respond to standard therapy. This study investigated the efficacy and safety profile of a modified DEP regimen in combination with PEG-aspargase (L-DEP) as a salvage therapy for refractory EBV-HLH. In this study from October 2014 to October 2015, 28 patients with refractory EBV-HLH received a L-DEP regimen at the Beijing Friendship Hospital, Capital Medical University. Treatment efficacy and adverse events were evaluated at 2 and 4 weeks after L-DEP treatment. Median EBV-DNA concentrations before and 2 weeks after receiving the L-DEP regimen were 9.6 × 105 (1.5 × 104 − 1 × 109) copies/mL and 2.2 × 105 (3.8 × 102 − 1.2 × 107) copies/mL, respectively; the post-treatment values were significantly lower than that of the pretreatment (P = 0.048). Nine of the 28 study patients achieved complete response (CR) and 15 partial response (PR), resulting in an overall response rate of 85.7 % (CR+PR). Four patients who did not achieve response died within 4 weeks of receiving L-DEP. Thirteen of the 24 patients who achieved partial or complete response received subsequent allogenic hematopoietic stem cell transplantation (allo-HSCT). Ten of these 13 patients survived until 1 March 2016. The major adverse effects of the L-DEP regimen were high serum amylase concentrations, abnormal liver function, and coagulation disorders. This study suggests that L-DEP is a safe and effective salvage therapy prior to allo-HSCT for refractory EBV-HLH and increases the possibility of such patients receiving allo-HSCT. A prospective multicenter large-scale clinical trial that aims to validate the L-DEP regimen for refractory EBV-HLH is currently underway (ClinicalTrails.gov Identifier: NCT02631109).
Review: In type 2 diabetes, adding dipeptidyl peptidase-4 inhibitors to sulphonylureas increases hypoglycemia
Authors: Michael Tanner
Journal: Annals of Internal Medicine (2016)

Source Citation Salvo F, Moore N, Arnaud M, et al. Addition of dipeptidyl peptidase-4 inhibitors to sulphonylureas and risk of hypoglycaemia: systematic review and meta-analysis. BMJ. 2016;353:i2231. 27142267
Incidence and recognition of acute respiratory distress syndrome in a UK intensive care unit
Authors: Charlotte Summers, Nanak R Singh, Linda Worpole, Rosalind Simmonds, Judith Babar, Alison M Condliffe, Kevin E Gunning, Andrew J Johnston, Edwin R Chilvers
Journal: Thorax (2016)

The reported incidence of ARDS is highly variable (2.5%–19% of intensive care unit (ICU) patients) and varies depending on study patient population used. We undertook a 6-month, prospective study to determine the incidence and outcome of ARDS in a UK adult University Hospital ICU. 344 patients were admitted during the study period, of these 43 (12.5%) were determined to have ARDS. Patients with ARDS had increased mortality at 28 days and 2 years post-diagnosis, and there was under-recognition of ARDS in both medical records and death certificattion. Our findings have implications for critical care resource planning.
Comparative Efficacy Among Chronic Phase-Chronic Myeloid Leukemia (CP-CML) Patients After Failure Of 2nd Generation Tyrosine Kinase Inhibitors (2G TKIs)
Authors: Jeff H. Lipton, Peter Bryden, Manpreet K Sidhu, Hui Huang, Lisa J McGarry, Stephanie Lustgarten, Beth Woods, Neil Hawkins
Journal: Blood (2013)
Minimal Residual Disease Monitored With Fluorescence In Situ Hybridization (FISH) In CD34+CD38- Population Predicts Clinical Outcome In Core Binding Factor Acute Myeloid Leukemia (CBF-AML)
Authors: Xiaoxia Hu, Libing Wang, Lei Gao, Sheng Xu, Shenglan Gong, Min Liu, Huiying Qiu, Xiaoqian Xu, Xiong Ni, Li Chen, Shuqing Lü, Jie Chen, Xianmin Song, Weiping Zhang, Jianmin Yang, Jianmin Wang
Journal: Blood (2013)
Population Evolution of <i>Helicobacter pylori</i> through Diversification in DNA Methylation and Interstrain Sequence Homogenization
Authors: Kenji K. Kojima, Yoshikazu Furuta, Koji Yahara, Masaki Fukuyo, Yuh Shiwa, Shin Nishiumi, Masaru Yoshida, Takeshi Azuma, Hirofumi Yoshikawa, Ichizo Kobayashi
Journal: Molecular Biology and Evolution (2016)

Decoding of closely related genomes is now revealing the process of population evolution. In bacteria, population divergence appears associated with a unique set of sequence-specific epigenetic DNA methylation systems, often within restriction-modification (RM) systems. They might define a unique gene expression pattern and limit genetic flux between lineages in population divergence. We addressed the contribution of methylation systems to population diversification in panmictic bacterial species, Helicobacter pylori, which shows an interconnected population structure through frequent mutual recombination. We analyzed complete genome sequences of 28 strains collected in Fukui, Japan. Their nucleotide sequences are closely related although fine-scale analyses revealed two subgroups likely reflecting human subpopulations. Their sequences are tightly connected by homologous recombination. Our extensive analysis of RM systems revealed an extreme variability in DNA methyltransferases, especially in their target recognition domains. Their diversity was, however, not immediately related to the genome sequence diversity, except for very closely related strains. An interesting exception is a hybrid strain, which likely has conserved the methylation gene repertoire from one parent but diversified in sequence by massive acquisition of fragmentary DNA sequences from the other parent. Our results demonstrate how a bacterial population can be extremely divergent in epigenetics and yet homogenized in sequence.
PWE-069 Colorectal cancer lymphatics display an altered phenotype associated with lymph node metastasis
Authors: D J Royston, S Clasper, D Baban, Y Cao, D G Jackson
Journal: Gut (2010)

<h3>Introduction</h3> Tumour cell metastasis to lymph nodes is a frequent clinical feature of colorectal cancer and often heralds a poor clinical outcome. Although tumoural lymphangiogenesis is assumed to contribute to this process there is little evidence to support any notion of a simple correlation between lymphatic vessel density and colorectal cancer metastasis. Growing evidence of complex functional and biochemical interactions between tumour cells and the tumour microvasculature imply that tumoural lymphatics may possess specific phenotypes capable of facilitating tumour cell entry and spread to draining lymph nodes. <h3>Methods</h3> We compared the RNA profile of primary lymphatic endothelial cells isolated from tumour and normal tissue using the lymph node metastasising murine T-241/VEGF-C fibrosarcoma model. These results were validated immunohistochemically in several human cancers, including colorectal cancer. The prognostic significance of two differentially expressed genes on tumoural lymphatics was assessed by immunofluorescence microscopy on a panel of mixed stage colorectal cancer tissues. <h3>Results</h3> We reveal significant differences in the expression of some 792 genes between normal and tumour lymphatic endothelial cells (ie, &gt;2× fold up/downregulation). These include genes that code for a variety of proteins including components of endothelial junctions, subendothelial matrix, and vessel growth/patterning. We investigated two of these differentially expressed genes in colorectal cancer; Endothelial Specific Adhesion Molecule (ESAM), a tight junction regulatory protein, and Endoglin (CD105), the transforming growth factor-β coreceptor. We reveal that ESAM and Endoglin are significantly upregulated on the lymphatics of colorectal cancer relative to normal tissue, with quantitative analysis of lymphatic vessel staining revealing a dramatic association between the incidence of ESAM positive tumour vessels and the presence of lymph node metastasis. <h3>Conclusion</h3> These findings reveal a remarkable degree of phenotypic plasticity in cancer lymphatics and provide new insight into the processes of lymphatic invasion and lymph node metastasis. The detailed characterisation of such qualitative changes may allow the development of better prognostic indicators in colorectal cancer and enlighten the search for improved anti-metastatic therapies.
Immunomodulation by HDAC inhibition: Results from a phase II study with entinostat and high-dose Interleukin 2 in renal cell carcinoma patients (CTEP#7870).
Authors: Roberto Pili, David I. Quinn, Hans J. Hammers, Paul Monk, Saby George, Tanya B. Dorff, Thomas Olencki, Li Shen, Alan Hutson, Richard Piekarz, Michael Anthony Carducci
Journal: Journal of Clinical Oncology (2016)

500 Background: Immunosuppressive factors such as regulatory T cells (Tregs) and myeloid-derived suppressive cells (MDSCs) limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been shown to have immunomodulatory effects. We have previously reported that the class I HDAC inhibitor entinostat has synergistic antitumor effects in combination with high dose interleukin-2 (IL-2) in a renal cell carcinoma model by down-regulating Foxp3 expression and function of Tregs. Thus, we have conducted a Phase I/II clinical study with entinostat and high dose IL-2 in patients (pts) with metastatic clear cell renal cell carcinoma. Methods: The primary objectives were to evaluate the safety, tolerability and efficacy of this combination strategy. The main eligibility criteria were clear cell histology and being fit to receive high dose IL-2. The phase I portion consisted of two dose levels of entinostat (3 and 5 mg, PO every14 days) and a fixed dose of IL-2 (600,000 units/kg every 8 hrs). To test our hypothesis, the fixed sample size at the Phase II dose level was 36 with a type I/II error of 10%. If 11 or more of the pts have a response, the hypothesis that the response rate is ≤ 20% is rejected. Results: Dose levels 1 and 2 were completed without DLTs and 5 mg entinostat was the Phase II recommended dose. No severe adverse events were observed during the first 45 days of treatment. The most common transient grade 3/4 toxicities were lymphopenia (50%), neutropenia (9%), and hypophosphatemia (6%). To date, we have enrolled 39 pts at dose level 2, and 35 have completed one cycle (84 days). Four pts were not evaluable. Twelve pts have achieved objective response (39%; 9 PR, 3 CR) with a median time to response of 81 days (55-96). The median PFS has not been reached with a median follow-up of 437 days (30-1428). Preliminary results show decreased Tregs and monocytic MDSCs following treatment and suggest an association of increased CD14 + /CD86 + and CD14 + HLADR + cells with objective response. Conclusions: The results from this phase I/II suggest that entinostat may increase the therapeutic effect of high dose IL-2 by modulating immunosuppressive cells (R21CA137649; U01CA70095). Clinical trial information: NCT01038778.
Topoisomerase II beta interacts with cohesin and CTCF at topological domain borders
Authors: Liis Uusküla-Reimand, Huayun Hou, Payman Samavarchi-Tehrani, Matteo Vietri Rudan, Minggao Liang, Alejandra Medina-Rivera, Hisham Mohammed, Dominic Schmidt, Petra Schwalie, Edwin J. Young, Jüri Reimand, Suzana Hadjur, Anne-Claude Gingras, Michael D. Wilson
Journal: Genome biology (2016)

Type II DNA topoisomerases (TOP2) regulate DNA topology by generating transient double stranded breaks during replication and transcription. Topoisomerase II beta (TOP2B) facilitates rapid gene expression and functions at the later stages of development and differentiation. To gain new insight into the genome biology of TOP2B, we used proteomics (BioID), chromatin immunoprecipitation, and high-throughput chromosome conformation capture (Hi-C) to identify novel proximal TOP2B protein interactions and characterize the genomic landscape of TOP2B binding at base pair resolution.Our human TOP2B proximal protein interaction network included members of the cohesin complex and nucleolar proteins associated with rDNA biology. TOP2B associates with DNase I hypersensitivity sites, allele-specific transcription factor (TF) binding, and evolutionarily conserved TF binding sites on the mouse genome. Approximately half of all CTCF/cohesion-bound regions coincided with TOP2B binding. Base pair resolution ChIP-exo mapping of TOP2B, CTCF, and cohesin sites revealed a striking structural ordering of these proteins along the genome relative to the CTCF motif. These ordered TOP2B-CTCF-cohesin sites flank the boundaries of topologically associating domains (TADs) with TOP2B positioned externally and cohesin internally to the domain loop.TOP2B is positioned to solve topological problems at diverse cis-regulatory elements and its occupancy is a highly ordered and prevalent feature of CTCF/cohesin binding sites that flank TADs.
Phase II Study of Enzastaurin in the Treatment of Relapsed/Refractory Mantle Cell Lymphoma.
Authors: Frank Morschhausser, Martin Wolf, John Seymour, Herve Tilly, Michael Pfreundschuh, Hanneke Kluin-Nelemans, John Raemaekers, Mars B. van’t Veer, Noel Milpied, Guillaume Cartron, Antonio Pezzutto, Andrew Spencer, Christelle Darstein, Donald Thornton, Martin Dreyling, Felix Reyes
Journal: Blood (2006)