tbuckley/cabot-search huggingface dataset:
Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase
Authors: Xiaoyang Dai, Juan Yan, Xuhong Fu, Qiuming Pan, Danni Sun, Yuan Xu, Jiang Wang, Litong Nie, Linjiang Tong, Aijun Shen, Mingyue Zheng, Min Huang, Minjia Tan, Hong Liu, Xun Huang, Jian Ding, Meiyu Geng
Journal: Clinical Cancer Research (2017)

Purpose: Recent epidemiological and clinical studies have suggested the benefit of aspirin for patients with cancer, which inspired increasing efforts to demonstrate the anticancer ability of aspirin and reveal the molecular mechanisms behind. Nevertheless, the anticancer activity and related mechanisms of aspirin remain largely unknown. This study aimed to confirm this observation, and more importantly, to investigate the potential target contributed to the anticancer of aspirin.Experimental Design: A homogeneous time-resolved fluorescence (HTRF) assay was used to examine the impact of aspirin on heparanase. Streptavidin pull-down, surface plasmon resonance (SPR) assay, and molecular docking were performed to identify heparanase as an aspirin-binding protein. Transwell, rat aortic rings, and chicken chorioallantoic membrane model were used to evaluate the antimetastasis and anti-angiogenesis effects of aspirin, and these phenotypes were tested in a B16F10 metastatic model, MDA-MB-231 metastatic model, and MDA-MB-435 xenograft model.Results: This study identified heparanase, an oncogenic extracellular matrix enzyme involved in cancer metastasis and angiogenesis, as a potential target of aspirin. We had discovered that aspirin directly binds to Glu225 region of heparanase and inhibits the enzymatic activity. Aspirin impeded tumor metastasis, angiogenesis, and growth in heparanase-dependent manner.Conclusions: In summary, this study has illustrated heparanase as a target of aspirin for the first time. It provides insights for a better understanding of the mechanisms of aspirin in anticancer effects, and offers a direction for the development of small-molecule inhibitors of heparanase. Clin Cancer Res; 23(20); 6267-78. ©2017 AACR.
Intracellular APOL1 Risk Variants Cause Cytotoxicity Accompanied by Energy Depletion
Authors: Daniel Granado, Daria Müller, Vanessa Krausel, Etty Kruzel-Davila, Christian Schuberth, Melanie Eschborn, Roland Wedlich-Söldner, Karl Skorecki, Hermann Pavenstädt, Ulf Michgehl, Thomas Weide
Journal: Journal of the American Society of Nephrology (2017)

Population genetic approaches have uncovered a strong association between kidney diseases and two sequence variants of the APOL1 gene, called APOL1 risk variant G1 and variant G2, compared with the nonrisk G0 allele. However, the mechanism whereby these variants lead to disease manifestation and, in particular, whether this involves an intracellular or extracellular pool of APOL1 remains unclear. Herein, we show a predominantly intracellular localization of APOL1 G0 and the renal risk variants, which localized to membranes of the endoplasmic reticulum in podocyte cell lines. This localization did not depend on the N-terminal signal peptide that mediates APOL1 secretion into the circulation. Additionally, a fraction of these proteins localized to structures surrounding mitochondria. In vitro overexpression of G1 or G2 lacking the signal peptide inhibited cell viability, triggered phosphorylation of stress-induced kinases, increased the phosphorylation of AMP-activated protein kinase, reduced intracellular potassium levels, and reduced mitochondrial respiration rates. These findings indicate that functions at intracellular membranes, specifically those of the endoplasmic reticulum and mitochondria, are crucial factors in APOL1 renal risk variant–mediated cell injury.
Phenetic Comparison of Prokaryotic Genomes Using k-mers
Authors: Maxime Déraspe, Frédéric Raymond, Sébastien Boisvert, Alexander Culley, Paul H. Roy, François Laviolette, Jacques Corbeil
Journal: Molecular Biology and Evolution (2017)

Bacterial genomics studies are getting more extensive and complex, requiring new ways to envision analyses. Using the Ray Surveyor software, we demonstrate that comparison of genomes based on their k-mer content allows reconstruction of phenetic trees without the need of prior data curation, such as core genome alignment of a species. We validated the methodology using simulated genomes and previously published phylogenomic studies of Streptococcus pneumoniae and Pseudomonas aeruginosa. We also investigated the relationship of specific genetic determinants with bacterial population structures. By comparing clusters from the complete genomic content of a genome population with clusters from specific functional categories of genes, we can determine how the population structures are correlated. Indeed, the strain clustering based on a subset of k-mers allows determination of its similarity with the whole genome clusters. We also applied this methodology on 42 species of bacteria to determine the correlational significance of five important bacterial genomic characteristics. For example, intrinsic resistance is more important in P. aeruginosa than in S. pneumoniae, and the former has increased correlation of its population structure with antibiotic resistance genes. The global view of the pangenome of bacteria also demonstrated the taxa-dependent interaction of population structure with antibiotic resistance, bacteriophage, plasmid, and mobile element k-mer data sets.
Individualized Dosing of Hydroxyurea for Children with Sickle Cell Anemia Using a Population Pharmacokinetic-Based Model: The TREAT Study
Authors: Patrick T. McGann, Min Dong, Anu Marahatta, Thad A. Howard, Tomoyuki Mizuno, Karen A. Kalinyak, Theodosia A. Kalfa, Punam Malik, Omar Niss, Charles T Quinn, Russell E. Ware, Alexander A. Vinks
Journal: Blood (2016)
Prospective evaluation of chronic organ damage in adult sickle cell patients: A seven‐year follow‐up study
Authors: Charlotte F. J. van Tuijn, Marein Schimmel, Eduard J. van Beers, Erfan Nur, Bart J. Biemond
Journal: American Journal of Hematology (2017)

Abstract Organ damage in sickle cell disease (SCD) is a crucial determinant for disease severity and prognosis. In a previous study, we analyzed the prevalence of SCD‐related organ damage and complications in adult sickle cell patients. We now describe a seven‐year follow‐up of this cohort.All patients from the primary analysis in 2006 ( n = 104), were included for follow‐up. Patients were screened for SCD‐related organ damage and complications (microalbuminuria, renal failure, elevated tricuspid regurgitation flow velocity (TRV) (≥2.5 m/seconds), retinopathy, iron overload, cholelithiasis, avascular osteonecrosis, leg ulcers, acute chest syndrome (ACS), stroke, priapism and admissions for vaso‐occlusive crises (VOC) biannually. Upon 7 years of follow‐up, progression in the prevalence of avascular osteonecrosis (from 12.5% to 20.4%), renal failure (from 6.7% to 23.4%), retinopathy (from 39.7% to 53.8%) was observed in the whole group. In HbSS/HbSβ 0 ‐thal patients also progression in microalbuminuria (from 34% to 45%) and elevated TRV (from 40% to 48%) was observed while hardly any progression in the prevalence of cholelithiasis, priapism, stroke or chronic ulcers was seen. The proportion of patients with at least one episode of ACS increased in the group of HbSS/HbSβ 0 ‐thal patients from 32% to 49.1%. In conclusion, 62% of the sickle cell patients in this prospective cohort study developed a new SCD‐related complication in a comprehensive care setting within 7 years of follow‐up. Although the hospital admission rate for VOC remained stable, multiple forms of organ damage increased substantially. These observations underline the need for continued screening for organ damage in all adult patients with SCD.
Microvesicles as Potential Biomarkers for the Identification of Senescence in Human Mesenchymal Stem Cells
Authors: Qian Lei, Teng Liu, Fei Gao, Hui Xie, Li Sun, Aiqi Zhao, Wenxiang Ren, Hao Guo, Liming Zhang, Hongxiang Wang, Zhichao Chen, An-Yuan Guo, Qiubai Li
Journal: Theranostics (2017)

Senescence in human mesenchymal stem cells (MSCs) not only contributes to organism aging and the development of a variety of diseases but also severely impairs their therapeutic properties as a promising cell therapy.Studies searching for efficient biomarkers that represent cellular senescence have attracted much attention; however, no single marker currently provides an accurate cell-free representation of cellular senescence.Here, we studied characteristics of MSC-derived microvesicles (MSC-MVs) that may reflect the senescence in their parental MSCs.We found that senescent late passage (LP) MSCs secreted higher levels of MSC-MVs with smaller size than did early passage (EP) MSCs, and the level of CD105+ MSC-MVs decreased with senescence in the parental MSCs.Also, a substantially weaker ability to promote osteogenesis in MSCs was observed in LP than EP MSC-MVs.Comparative analysis of RNA sequencing showed the same trend of decreasing number of highly-expressed miRNAs with increasing number of passages in both MSCs and MSC-MVs.Most of the highly-expressed genes in LP MSCs and the corresponding MSC-MVs were involved in the regulation of senescence-related diseases, such as Alzheimer's disease.Furthermore, based on the miRNA profiling, transcription factors (TF) and genes regulatory networks of MSC senescence, and the datasets from GEO database, we confirmed that expression of miR-146a-5p in MSC-MVs resembled the senescent state of their parental MSCs.Our findings provide evidence that MSC-MVs are a key factor in the senescence-associated secretory phenotype of MSCs and demonstrate that their integrated characteristics can dynamically reflect the senescence state of MSCs representing a potential biomarker for monitoring MSC senescence.
Does the presence or absence of type VII collagen expression in individuals with recessive dystrophic epidermolysis bullosa have implications for the risk of developing squamous cell carcinoma
Authors: GA Cox, C Pourreyron, A Volz, EA O'Toole, M Chen, L Bruckner-Tuderman, JC Salas-Alanis, IM Leigh, AP South, John McGrath
Journal: British Journal of Dermatology (2007)
Biomarkers predict enhanced clinical outcomes with afatinib versus methotrexate in patients with second-line recurrent and/or metastatic head and neck cancer
Authors: E.E.W. Cohen, L.F. Licitra, B. Burtness, J. Fayette, T. Gauler, P.M. Clement, J.J. Grau, J.M. del Campo, A. Mailliez, R.I. Haddad, J.B. Vermorken, M. Tahara, J. Guigay, L. Geoffrois, M.C. Merlano, N. Dupuis, N. Krämer, X.J. Cong, N. Gibson, F. Solca, E. Ehrnrooth, J.-P.H. Machiels
Journal: Annals of Oncology (2017)

In the phase III LUX-Head & Neck 1 (LUX-H&N1) trial, second-line afatinib significantly improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Here, we evaluated association of prespecified biomarkers with efficacy outcomes in LUX-H&N1.Randomized patients with R/M HNSCC and progression following ≥2 cycles of platinum therapy received afatinib (40 mg/day) or methotrexate (40 mg/m2/week). Tumor/serum samples were collected at study entry for patients who volunteered for inclusion in biomarker analyses. Tumor biomarkers, including p16 (prespecified subgroup; all tumor subsites), EGFR, HER2, HER3, c-MET and PTEN, were assessed using tissue microarray cores and slides; serum protein was evaluated using the VeriStrat® test. Biomarkers were correlated with efficacy outcomes.Of 483 randomized patients, 326 (67%) were included in the biomarker analyses; baseline characteristics were consistent with the overall study population. Median PFS favored afatinib over methotrexate in patients with p16-negative [2.7 versus 1.6 months; HR 0.70 (95% CI 0.50-0.97)], EGFR-amplified [2.8 versus 1.5 months; HR 0.53 (0.33-0.85)], HER3-low [2.8 versus 1.8 months; HR 0.57 (0.37-0.88)], and PTEN-high [1.6 versus 1.4 months; HR 0.55 (0.29-1.05)] tumors. Afatinib also improved PFS in combined subsets of patients with p16-negative and EGFR-amplified tumors [2.7 versus 1.5 months; HR 0.47 (0.28-0.80)], and patients with p16-negative tumors who were EGFR therapy-naïve [4.0 versus 2.4 months; HR 0.55 (0.31-0.98)]. PFS was improved in afatinib-treated patients who were VeriStrat 'Good' versus 'Poor' [2.7 versus 1.5 months; HR 0.71 (0.49-0.94)], but no treatment interaction was observed. Afatinib improved tumor response versus methotrexate in all subsets analyzed except for those with p16-positive disease (n = 35).Subgroups of HNSCC patients who may achieve increased benefit from afatinib were identified based on prespecified tumor biomarkers (p16-negative, EGFR-amplified, HER3-low, PTEN-high). Future studies are warranted to validate these findings.NCT01345682.
PSMA-Targeted Theranostic Nanocarrier for Prostate Cancer
Authors: Orielyz Flores, Santimukul Santra, Charalambos Kaittanis, Rania Bassiouni, Amr S Khaled, Annette R. Khaled, Jan Grimm, J Manuel Perez
Journal: Theranostics (2017)

Herein, we report the use of a theranostic nanocarrier (Folate-HBPE(CT20p)) to deliver a therapeutic peptide to prostate cancer tumors that express PSMA (folate hydrolase 1). The therapeutic peptide (CT20p) targets and inhibits the chaperonin-containing TCP-1 (CCT) protein-folding complex, is selectively cytotoxic to cancer cells, and is non-toxic to normal tissue. With the delivery of CT20p to prostate cancer cells via PSMA, a dual level of cancer specificity is achieved: (1) selective targeting to PSMA-expressing prostate tumors, and (2) specific cytotoxicity to cancer cells with minimal toxicity to normal cells. The PSMA-targeting theranostic nanocarrier can image PSMA-expressing cells and tumors when a near infrared dye is used as cargo. Meanwhile, it can be used to treat PSMA-expressing tumors when a therapeutic, such as the CT20p peptide, is encapsulated within the nanocarrier. Even when these PSMA-targeting nanocarriers are taken up by macrophages, minimal cell death is observed in these cells, in contrast with doxorubicin-based therapeutics that result in significant macrophage death. Incubation of PSMA-expressing prostate cancer cells with the Folate-HBPE(CT20p) nanocarriers induces considerable changes in cell morphology, reduction in the levels of integrin β1, and lower cell adhesion, eventually resulting in cell death. These results are relevant as integrin β1 plays a key role in prostate cancer invasion and metastatic potential. In addition, the use of the developed PSMA-targeting nanocarrier facilitates the selective in vivo delivery of CT20p to PSMA-positive tumor, inducing significant reduction in tumor size.
Response to Letter Regarding Article, “Risk Factors for Coarctation of the Aorta on Prenatal Ultrasound: A Systematic Review and Meta-Analysis”
Authors: Alessandra Familiari, Maddalena Morlando, Sven-Erik Sonesson, Giuseppe Rizzo, Ganesh Acharya, Lamberto Manzoli, Francesco D’Antonio
Journal: Circulation (2017)

In Response:We thank Ceylan for his interest in our work and the interesting points he raised.We agree that the size of the ascending aorta did not signal coarctation (CoA) because of problems associated with diameter measurements (which are frequently measured on long-axis images) and the small number of cases included.We acknowledge this major weakness of our systematic review. 1 Although not statistically significant, a trend toward smaller ascending aorta diameters of fetuses affected by CoA was observed.However, we find it unreasonable, in a systematic review, to judge reported diagnoses, which is the responsibility of authors, reviewers, and editors at the point of publication of the primary study.Pathophysiology of CoA has not been completely elucidated yet.Although a progressive reduction of antegrade blood flow through the aortic isthmus is likely to be responsible for the underdevelopment of the aortic arch in a large majority of CoA cases, migration or extension of ductal tissue into the wall of the fetal thoracic aorta could be responsible for those with juxta-ductal CoA, which become significant as ductus closes and are less likely to be affected by a reduction in the diameter of the ascending aorta in utero. 2 A stratified analysis according to the subtypes of CoA (pre-versus juxta-ductal) could not be performed because of the lack of information on ascending aorta diameter on individual cases affected by CoA.4][5] What is more relevant, however, is the fact that, despite the presence of a physiological right ventricular dominance, a significant discrepancy in the size of the cardiac chambers during the third trimester of pregnancy is the main ultrasound feature that raises the suspicion of CoA, although the diagnostic performance is relatively poor on its own.
A Missense Mutation in the Extracellular Domain of αENaC Causes Liddle Syndrome
Authors: Mahdi Salih, Ivan Gautschi, Miguel X. van Bemmelen, Michael Di Benedetto, Alice S. Brooks, Dorien Lugtenberg, Laurent Schild, Ewout J. Hoorn
Journal: Journal of the American Society of Nephrology (2017)

Liddle syndrome is an autosomal dominant form of hypokalemic hypertension due to mutations in the β - or γ -subunit of the epithelial sodium channel (ENaC). Here, we describe a family with Liddle syndrome due to a mutation in α ENaC. The proband was referred because of resistant hypokalemic hypertension, suppressed renin and aldosterone, and no mutations in the genes encoding β - or γ ENaC. Exome sequencing revealed a heterozygous, nonconservative T&gt;C single-nucleotide mutation in α ENaC that substituted Cys479 with Arg (C479R). C479 is a highly conserved residue in the extracellular domain of ENaC and likely involved in a disulfide bridge with the partner cysteine C394. In oocytes, the C479R and C394S mutations resulted in similar twofold increases in amiloride-sensitive ENaC current. Quantification of mature cleaved α ENaC in membrane fractions showed that the number of channels did not increase with these mutations. Trypsin, which increases open probability of the channel by proteolytic cleavage, resulted in significantly higher currents in the wild type than in C479R or C394S mutants. In summary, a mutation in the extracellular domain of α ENaC causes Liddle syndrome by increasing intrinsic channel activity. This mechanism differs from that of the β - and γ -mutations, which result in an increase in channel density at the cell surface. This mutation may explain other cases of patients with resistant hypertension and also provides novel insight into ENaC activation, which is relevant for kidney sodium reabsorption and salt-sensitive hypertension.
OC-051 Oesophageal physiology abnormalities in patients with joint hypermobility syndrome
Authors: J Barragry, KC Fragkos, E Paulon, A Raeburn, R Sweis, A Emmanuel, N Zarate-Lopez
Journal: Gut (2017)

Introduction  EDS-hypermobility type/joint hypermobility syndrome (JHS) is frequently associated with functional gut symptoms. Altered pain processing and visceral hypersensitivity have been proposed to play a role in this association. However, co-existent gut motor dysfunction secondary to underlying abnormal connective tissue might also play a role. The aim of this study is to investigate the clinical presentation and oesophageal physiology abnormalities in a large cohort of patients with JHS referred for investigation of symptoms of reflux and dysphagia.  Method  Forty-nine consecutive patients with JHS, previously diagnosed by a rheumatology consultant, were referred to the gastrointestinal physiology department for further investigation of upper GI symptoms. Twenty-five consecutive patients without JHS, referred over a period of one month, were used as controls. Patients underwent high resolution oesophageal manometry (HRM) and combined multichannel impedance-pH monitoring (MII-pH). Oesophageal physiology data and clinical presentation were reviewed retrospectively. Manometry analysis was done according to the Chicago classification. MII-pH recordings were analysed for total acid time exposure and for reflux-symptom association. Results are reported in percentages and associations were examined with chi-square and fisher tests in SPSS 22.  Results  The majority of patients were females (45 F, 4 M, mean age 40 years for JHS vs 16 F, 9 M, mean age 48 years for controls). Dysphagia was the most prevalent symptom in JHS (70% vs 40% in controls, p 0.05). Oesophageal hypomotility was present in 41% of patients with JHS and 48% of controls (p>0.05). A hypotensive lower oesophageal sphincter (LOS) was described in 21% of patients with JHS vs 44% of controls (p 0.05). Dysphagia, heartburn, and excessive acid reflux exposure were not more frequent in patients with JHS and oesophageal hypomotility (p>0.05).  Conclusion  This is the largest cohort of patients with JHS investigated with oesophageal physiology techniques for assessment of upper GI symptoms. Dysphagia was disproportionately reported by patients with JHS. However, this was not associated with an increased prevalence of oesophageal hypomotility. Correlation between symptoms and oesophageal physiology abnormalities is poor and suggest visceral hypersensitivity or hypervigilance may play a role in symptom generation.  Disclosure of Interest  None Declared
Use of Bisphosphonates and Risk of Breast Cancer in a French Cohort of Postmenopausal Women
Authors: Agnès Fournier, Sylvie Mesrine, Amandine Gelot, Guy Fagherazzi, Laura Baglietto, Françoise Clavel-Chapelon, Marie-Christine Boutron-Ruault, Nathalie Chabbert-Buffet
Journal: Journal of Clinical Oncology (2017)

Purpose To assess whether bisphosphonate (BP) use is associated with decreased breast cancer incidence in a cohort of postmenopausal women. Methods The study population included 64,438 postmenopausal women participating in the French E3N (Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale) prospective cohort, with data self-reported in biennial questionnaires matched with data from a drug reimbursement database. Exposure to BPs and the use of other osteoporosis treatments during follow-up were determined using reimbursement data. Other covariates (breast cancer risk factors, clinical risk factors for osteoporotic fractures, and bone mineral density surveillance) originated from the questionnaires. Hazard ratios (HRs) of breast cancer were estimated using Cox proportional hazards models, considering exposure as a time-varying variable. Results Over an average of 7.2 years of follow-up (2004 to 2011), 2,407 first primary breast cancer cases were identified. The HR of breast cancer associated with exposure to BPs was 0.98 (95% CI, 0.85 to 1.12). We found no effect modification by age, body mass index, time since menopause, use of hormone replacement therapy, use of calcium supplements, or use of vitamin D supplements. There was no heterogeneity across BP molecules and no trend according to cumulative dose, duration of use, or time since last use. We observed a decrease in breast cancer risk restricted to the year after treatment initiation (HR, 0.56; 95% CI, 0.36 to 0.87), which was likely explained by healthy screenee bias. Finally, we did not find any variation in HRs across breast carcinomas defined by their estrogen receptor or invasive or in situ status. Conclusion In our observational cohort of postmenopausal women observed from 2004 to 2011, BP use, likely prescribed for the management of osteoporosis, was not associated with decreased breast cancer incidence.