tbuckley/cabot-search huggingface dataset:
The P2X7 receptor regulates cell survival, migration and invasion of pancreatic ductal adenocarcinoma cells
Authors: Andrea Giannuzzo, Stine Falsig Pedersen, Ivana Novak
Journal: Molecular Cancer (2015)

Pancreatic ductal adenocarcinoma (PDAC) is presently one of the cancers with the worst survival rates and least effective treatments. Moreover, total deaths due to PDAC are predicted to increase in the next 15 years. Therefore, novel insights into basic mechanism of PDAC development and therapies are needed. PDAC is characterized by a complex microenvironment, in which cancer and stromal cells release different molecules, such as ATP. ATP can be transported and/or exocytosed from active cancer cells and released from dying cells in the necrotic core of the cancer. We hypothesized that one of the ATP receptors, the P2X7 receptor (P2X7R) could be an important player in PDAC behaviour.We determined the expression (real time PCR and Western blot) and localization (immunofluorescence) of P2X7R in human PDAC cell lines (AsPC-1, BxPC-3, Capan-1, MiaPaCa-2, Panc-1) and a "normal" human pancreatic duct epithelial cell line (HPDE). The function of P2X7R in proliferation (BrdU assay), migration (wound assay) and invasion (Boyden chamber with matrigel) was characterized. Furthermore, we studied P2X7R-dependent pore formation (YoPro-1 assay) and cell death (caspase and annexin V / propidium iodide assays).We found higher expression of P2X7R protein in PDAC compared to HPDE cells. P2X7R had notable disparate effects on PDAC survival. Firstly, high concentrations of ATP or the specific P2X7R agonist, BzATP, had cytotoxic effects in all cell lines, and cell death was mediated by necrosis. Moreover, the P2X7R-pore antagonist, A438079, prevented ATP-induced pore formation and cell death. Second, in basal conditions and with low concentrations of ATP/BzATP, the P2X7R allosteric inhibitor AZ10606120 reduced proliferation in all PDAC cell lines. P2X7R also affected other key characteristics of cancer cell behavior. AZ10606120 reduced cell migration and invasion in PDAC cell lines compared to that of untreated/vehicle-treated control cells, and stimulation with sub-millimolar concentrations of ATP or BzATP substantially increased cell invasion.PDAC cell lines overexpress P2X7R and the receptor plays crucial roles in cell survival, migration and invasion. Therefore, we propose that drugs targeting P2X7R could be exploited in therapy of pancreatic cancer.
Recombination Rate Variation Modulates Gene Sequence Evolution Mainly via GC-Biased Gene Conversion, Not Hill–Robertson Interference, in an Avian System
Authors: Paulina Bolívar, Carina F. Mugal, Alexander Nater, Hans Ellegren
Journal: Molecular Biology and Evolution (2015)

The ratio of nonsynonymous to synonymous substitution rates (ω) is often used to measure the strength of natural selection. However, ω may be influenced by linkage among different targets of selection, that is, Hill-Robertson interference (HRI), which reduces the efficacy of selection. Recombination modulates the extent of HRI but may also affect ω by means of GC-biased gene conversion (gBGC), a process leading to a preferential fixation of G:C ("strong," S) over A:T ("weak," W) alleles. As HRI and gBGC can have opposing effects on ω, it is essential to understand their relative impact to make proper inferences of ω. We used a model that separately estimated S-to-S, S-to-W, W-to-S, and W-to-W substitution rates in 8,423 avian genes in the Ficedula flycatcher lineage. We found that the W-to-S substitution rate was positively, and the S-to-W rate negatively, correlated with recombination rate, in accordance with gBGC but not predicted by HRI. The W-to-S rate further showed the strongest impact on both dN and dS. However, since the effects were stronger at 4-fold than at 0-fold degenerated sites, likely because the GC content of these sites is farther away from its equilibrium, ω slightly decreases with increasing recombination rate, which could falsely be interpreted as a consequence of HRI. We corroborated this hypothesis analytically and demonstrate that under particular conditions, ω can decrease with increasing recombination rate. Analyses of the site-frequency spectrum showed that W-to-S mutations were skewed toward high, and S-to-W mutations toward low, frequencies, consistent with a prevalent gBGC-driven fixation bias.
Stool consistency is strongly associated with gut microbiota richness and composition, enterotypes and bacterial growth rates
Authors: Doris Vandeputte, Gwen Falony, Sara Vieira-Silva, Raul Y Tito, Marie Joossens, Jeroen Raes
Journal: Gut (2015)

<h3>Objective</h3> The assessment of potentially confounding factors affecting colon microbiota composition is essential to the identification of robust microbiome based disease markers. Here, we investigate the link between gut microbiota variation and stool consistency using Bristol Stool Scale classification, which reflects faecal water content and activity, and is considered a proxy for intestinal colon transit time. <h3>Design</h3> Through 16S rDNA Illumina profiling of faecal samples of 53 healthy women, we evaluated associations between microbiome richness, Bacteroidetes:Firmicutes ratio, enterotypes, and genus abundance with self-reported, Bristol Stool Scale-based stool consistency. Each sample's microbiota growth potential was calculated to test whether transit time acts as a selective force on gut bacterial growth rates. <h3>Results</h3> Stool consistency strongly correlates with all known major microbiome markers. It is negatively correlated with species richness, positively associated to the Bacteroidetes:Firmicutes ratio, and linked to <i>Akkermansia</i> and <i>Methanobrevibacter</i> abundance. Enterotypes are distinctly distributed over the BSS-scores. Based on the correlations between microbiota growth potential and stool consistency scores within both enterotypes, we hypothesise that accelerated transit contributes to colon ecosystem differentiation. While shorter transit times can be linked to increased abundance of fast growing species in Ruminococcaceae-<i>Bacteroides</i> samples, hinting to a washout avoidance strategy of faster replication, this trend is absent in <i>Prevotella</i>-enterotyped individuals. Within this enterotype adherence to host tissue therefore appears to be a more likely bacterial strategy to cope with washout. <h3>Conclusions</h3> The strength of the associations between stool consistency and species richness, enterotypes and community composition emphasises the crucial importance of stool consistency assessment in gut metagenome-wide association studies.
PERTINENT (a substudy of the EUROPA trial): a persistent legacy: EXPERTS' PERSPECTIVE
Authors: J. C. Kaski, L. Consuegra-Sanchez
Journal: Cardiovascular Research (2012)

This editorial refers to an article by C. Ceconi et al . [9][1] published in Cardiovascular Research in 2007. It is accompanied by a retrospective editorial by two authors of that original article, R. Ferrari and C. Ceconi (doi: 10.1093/cvr/CVS165) as part of this Spotlight on Landmark Papers in Cardiovascular Research . 

Endothelial activation and dysfunction—usually associated with traditional cardiovascular disease risk factors and increased oxidative stress—initiate the atherosclerotic process. In patients with coronary artery disease (CAD), endothelial dysfunction results in abnormal coronary artery vasomotion, increased leucocyte adhesion to the vascular wall, platelet activation, and the release of pro-inflammatory molecules, all of which contribute to both the atherogenic process and atheromatous plaque growth. These events largely result from reduced nitric oxide (NO) production and bioavailability as well as the reduced expression and activity of endothelial nitric oxide synthase (eNOS), which can itself become a pro-atherogenic stimulus promoting an increase in oxidative stress.1,2 Prior to the publication of the EUROPA trial, several relatively small studies had suggested a correlation between coronary endothelial dysfunction and the occurrence of adverse events in patients with CAD.3–5 The important goal of improving endothelial dysfunction stimulated the development of therapies aimed at reversing or slowing down the processes leading to atherogenesis and vascular dysfunction. In this regard, the large EUROPA trial6 made an important contribution to the field. The study assessed whether the administration of the angiotensin-converting enzyme (ACE) inhibitor perindopril reduced …

 [1]: #ref-9
Infection Exposure Is a Causal Factor in B-cell Precursor Acute Lymphoblastic Leukemia as a Result of<i>Pax5</i>-Inherited Susceptibility
Authors: Alberto Martín-Lorenzo, Julia Hauer, Carolina Vicente-Dueñas, Franziska Auer, Inés González-Herrero, Idoia García-Ramírez, Sebastian Ginzel, Ralf Thiele, Stefan N. Constantinescu, Christoph Bartenhagen, Martin Dugas, Michael Gombert, Daniel Schäfer, Oscar Blanco, Andrea Mayado, Alberto Orfao, Diego Alonso-López, Javier De Las Rivas, César Cobaleda, Maria Begoña García-Cenador, Francisco Javier García-Criado, Isidro Sánchez-García, Arndt Borkhardt
Journal: Cancer Discovery (2015)

Abstract Earlier in the past century, infections were regarded as the most likely cause of childhood B-cell precursor acute lymphoblastic leukemia (pB-ALL). However, there is a lack of relevant biologic evidence supporting this hypothesis. We present in vivo genetic evidence mechanistically connecting inherited susceptibility to pB-ALL and postnatal infections by showing that pB-ALL was initiated in Pax5 heterozygous mice only when they were exposed to common pathogens. Strikingly, these murine pB-ALLs closely resemble the human disease. Tumor exome sequencing revealed activating somatic, nonsynonymous mutations of Jak3 as a second hit. Transplantation experiments and deep sequencing suggest that inactivating mutations in Pax5 promote leukemogenesis by creating an aberrant progenitor compartment that is susceptible to malignant transformation through accumulation of secondary Jak3 mutations. Thus, treatment of Pax5+/− leukemic cells with specific JAK1/3 inhibitors resulted in increased apoptosis. These results uncover the causal role of infection in pB-ALL development. Significance: These results demonstrate that delayed infection exposure is a causal factor in pB-ALL. Therefore, these findings have critical implications for the understanding of the pathogenesis of leukemia and for the development of novel therapies for this disease. Cancer Discov; 5(12); 1328–43. ©2015 AACR. See related commentary by Greaves and Müschen, p. 1244. This article is highlighted in the In This Issue feature, p. 1225
High-dose fractionated total-body irradiation, etoposide, and cyclophosphamide followed by autologous stem-cell support in patients with malignant lymphoma.
Authors: C H Weaver, F B Petersen, F R Appelbaum, W I Bensinger, O Press, P Martin, B Sandmaier, H J Deeg, J A Hansen, M Brunvand
Journal: Journal of Clinical Oncology (1994)

PURPOSE To evaluate a high-dose treatment regimen of fractionated total-body irradiation (TBI), etoposide, and cyclophosphamide (Cy) followed by autologous stem-cell transplantation (ASCT) in patients with malignant lymphoma. PATIENTS AND METHODS Fifty-three patients with non-Hodgkin's lymphoma (NHL; n = 43) or Hodgkin's disease (HD; n = 10) received 12.0 Gy of fractionated TBI, etoposide 60 mg/kg, and Cy 100 mg/kg followed by infusion of autologous hematopoietic stem cells. RESULTS Thirty-one of 53 patients are alive a median of 643 (range, 177 to 1,144) days after transplant. The 2 year Kaplan-Meier (K-M) estimates of survival, event-free survival (EFS), and relapse for all 53 patients were 54%, 45%, and 43%, respectively. Sixteen of 24 patients with less advanced disease and 10 of 29 patients with more advanced disease survive free of disease for K-M estimates of EFS of 61% and 31%, respectively (P = .006). The K-M estimates of relapse were 34% for patients with less advanced disease and 53% (P = .05) for patients with more advanced disease. The K-M estimates of dying from causes other than relapse were 8% in patients with less versus 25% in patients with more advanced disease (P = .09). CONCLUSION These data indicate that approximately 60% of patients transplanted early after failure of initial therapy for malignant lymphoma are projected to be disease-free more than 2 years after treatment with fractionated TBI, etoposide, and Cy and infusion of autologous hematopoietic stem cells. The transplant-related mortality rate is low and relapse is the main cause of treatment failure in patients with less advanced disease. For patients with more advanced disease, the K-M estimates of both transplant-related deaths (25%) and relapse (53%) remain major problems.
Pathogenicity of a Viral Strain (RPL12) Causing Avian Visceral Lymphomatosis and Related Neoplasms. III. Influence of Host Age and Route of Inoculation
Authors: B R BURMESTER, A K FONTES, W G WALTER
Journal: JNCI Journal of the National Cancer Institute (1960)

Seven experiments were conducted, with 6,200 White Leghorn chickens of inbred line 151, on the disease response of chickens to strain RPL12 virus, to study the influence of age of the chicken at the time of inoculation, the route of inoculation, or other methods of exposure. Chickens inoculated at 1 day of age with moderately large doses of virus died primarily of erythroblastosis, and the sensitivity to this response decreased with the various routes in the following order: intramedullary, intravenous, intraperitoneal, intracerebral, intramuscular, and subcutaneous. The 2 natural routes, oral and nasal, caused a much lower response than any of the parenteral routes, and most of the mortality was due to visceral lymphomatosis. Age of the chicken at the time of inoculation had a profound effect on the magnitude of the response obtained. Sensitivity of chickens to large doses, given intravenously and resulting primarily in erythroblastosis, increased slightly or not at all for the first 2 to 3 weeks of life, then decreased at a uniform rate until the chickens were at least 12 weeks of age. A more rapid decrease in sensitivity with no delay was obtained when large doses were inoculated intraperitoneally. Sensitivity of chickens to small doses, given intravenously and resulting primarily in visceral lymphomatosis, decreased uniformly from the 1st day and at a rate similar to that obtained with large doses given intravenously. Sensitivity of chickens given large doses by the oral and nasal routes, which resulted primarily in visceral lymphomatosis, decreased rapidly during the first 2 to 3 weeks of life, after which the decrease was much slower. Certain RPL12 virus preparations caused a high incidence of osteopetrosis when intravenous inoculations were made at 1 day of age. This response decreased rapidly with an increase in age at inoculation, so that the percent of chickens with osteopetrosis, inoculated at 3 weeks of age, was only one tenth that of chickens inoculated at 1 day of age.
Evaluation of Brain Imaging Techniques in Mental Illness
Authors: Nancy C. Andreasen
Journal: Annual Review of Medicine (1988)

Brain imaging is increasingly applied in psychiatry, both for clinical evaluation and as a research tool. Computerized tomography (CT) and magnetic resonance imaging (MRI) have documented that structural brain abnormalities occur in some types of psychiatric patients, particularly those who suffer from schizophrenia. Dynamic imaging techniques such as single-photon emission computed tomography (SPECT) and positron emission tomography (PET) have documented decreased temporoparietal activity in Alzheimer’s disease, hypofrontality in schizophrenia, and a variety of abnormalities in affective and anxiety disorders. These techniques promise to teach us a great deal about the underlying neural mechanisms in mental illness.
Detection of K-ras point mutations in sputum from patients with adenocarcinoma of the lung by point-EXACCT.
Authors: V A Somers, A M Pietersen, P H Theunissen, F B Thunnissen
Journal: Journal of Clinical Oncology (1998)

PURPOSE Kirsten ras (K-ras) point mutations are found in 30% to 56% of pulmonary adenocarcinomas by means of highly sensitive techniques. Recently, the Point-EXACCT (point mutation detection using exonuclease amplification coupled capture technique) method was described, which detected one cell with a mutation in 15,000 normal cells. The aim of this study was to examine whether K-ras point mutations could be found with this rapid method in the sputum of patients with adenocarcinoma of the lung. PATIENTS AND METHODS DNA from paraffin-embedded adenocarcinoma and corresponding sputum samples were analyzed for mutations of the K-ras gene. Twenty-eight biopsy specimens and 54 sputum samples of 22 patients were used for amplification and K-ras codon 12 point mutation detection. RESULTS In 11 of 22 patients (50%), a mutation in K-ras codon 12 was shown in the tumor sample. In five of 11 patients (45%) with a K-ras mutation in the tumor, the same type of mutation was identified in at least one sputum sample. A mutation could not be detected in any of the sputum samples from patients with a K-ras-negative tumor. Time between K-ras point mutation detection in sputum and clinical diagnosis of lung cancer varied from 1 month to almost 4 years. In two of the five patients with K-ras-positive sputum specimens, malignant cells were found with cytologic examination. CONCLUSION Point-EXACCT is suitable for the detection of K-ras point mutations in sputum samples of patients with adenocarcinoma of the lung. This approach may be an important adjunct to cytology in the early diagnosis of lung cancer.
Consequences of Phosphate Imbalance
Authors: Y N Berner, M Shike
Journal: Annual Review of Nutrition (1988)

Phosphorus is the sixth most abundant element in the body after oxygen, hydrogen, carbon, nitrogen, and calcium. It comprises about 1% of the total body weight of humans. Eighty-five percent of it is stored in the bone in the form of hydroxyapatite crystal; 14% is in the soft tissues in the form of energy-storing bonds with nucleotides (ATP, GTP), nucleic acids in chromosomes and ribosomes, 2,3-DPG in the red blood cells, and phospholipids in the cells' membranes. Less than 1% is in the extracellular fluids. Phosphate balance is maintained by multiple systems. The gut is responsible for the absorption of two thirds of the 4-30 mg/kg/day of phosphate intake. Absorption sites are all along the gut; in humans the most active site is the jejunum. The kidney filters 90% of the plasma phosphate and reabsorbs it in the tubuli. In states of hypophosphatemia the kidney can reabsorb the filtered phosphates very efficiently, reducing the amount excreted in the urine virtually to zero. The healthy kidney can excrete high loads of phosphate and rid the body of phosphate overload. Through the vitamin D-PTH axis the endocrine system regulates the phosphate balance by influencing the kidney, gut, and bone. Other hormones, including thyroid, insulin, glucagon, glucocorticosteroid, and thyrocalcitonin, play a lesser role in regulation of phosphate metabolism. Because of the complex control of phosphate homeostasis, various clinical conditions may lead to hypophosphatemia. These include nutritional repletion, gastrointestinal malabsorption, use of phosphate binders, starvation, diabetes mellitus, and increased urinary losses due to tubular dysfunction. The clinical picture of phosphate depletion is manifested in different organs and is due mainly to the fall in intracellular levels of ATP and decreased availability of oxygen to the tissues, secondary to 2,3-DPG depletion. The various manifestations of phosphate depletion are listed in Table 2. The treatment of hypophosphatemia consists of administering enteral or parenteral phosphate salts. An important aspect of dealing with the potentially serious effects of phosphate depletion is to prevent the depletion from happening in the first place. Hyperphosphatemia can occur in renal failure, hemolysis, tumor lysis syndrome, and rhabdomyolysis. The treatment of hyperphosphatemia usually consists of fluid administration (in the absence of kidney failure). In chronic hyperphosphatemia, phosphate binders such as aluminum and magnesium salts can reduce the phosphate load. The use of these phosphate binders is limited by their potential side effects.
Review: In older patients with AF or acute VTE, some DOACs reduce thrombotic events and major bleeding
Authors: Richard H. White
Journal: Annals of Internal Medicine (2015)

Source Citation Sharma M, Cornelius VR, Patel JP, Davies JG, Molokhia M. Efficacy and harms of direct oral anticoagulants in the elderly for stroke prevention in atrial fibrillation and secondary prevention of venous thromboembolism: systematic review and meta-analysis. Circulation. 2015;132:194-204. 25995317
Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine
Authors: Aurélie Ladang, Francesca Rapino, Lukas C. Heukamp, Lars Tharun, Kateryna Shostak, Damien Hermand, Sylvain Delaunay, Iva Klevernic, Zheshen Jiang, Nicolas Jacques, Diane Jamart, Valérie Migeot, Alexandra Florin, Serkan Göktuna, Brigitte Malgrange, Owen J. Sansom, Laurent Nguyen, Reinhard Büttner, Pierre Close, Alain Chariot
Journal: The Journal of Experimental Medicine (2015)

Tumor initiation in the intestine can rapidly occur from Lgr5+ crypt columnar stem cells. Dclk1 is a marker of differentiated Tuft cells and, when coexpressed with Lgr5, also marks intestinal cancer stem cells. Here, we show that Elp3, the catalytic subunit of the Elongator complex, is required for Wnt-driven intestinal tumor initiation and radiation-induced regeneration by maintaining a subpool of Lgr5+/Dclk1+/Sox9+ cells. Elp3 deficiency dramatically delayed tumor appearance in Apc-mutated intestinal epithelia and greatly prolonged mice survival without affecting the normal epithelium. Specific ablation of Elp3 in Lgr5+ cells resulted in marked reduction of polyp formation upon Apc inactivation, in part due to a decreased number of Lgr5+/Dclk1+/Sox9+ cells. Mechanistically, Elp3 is induced by Wnt signaling and promotes Sox9 translation, which is needed to maintain the subpool of Lgr5+/Dclk1+ cancer stem cells. Consequently, Elp3 or Sox9 depletion led to similar defects in Dclk1+ cancer stem cells in ex vivo organoids. Finally, Elp3 deficiency strongly impaired radiation-induced intestinal regeneration, in part because of decreased Sox9 protein levels. Together, our data demonstrate the crucial role of Elp3 in maintaining a subpopulation of Lgr5-derived and Sox9-expressing cells needed to trigger Wnt-driven tumor initiation in the intestine.
Adjuvant chemotherapy of breast cancer: a promising experiment or standard practice?
Authors: I C Henderson
Journal: Journal of Clinical Oncology (1985)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1985.3.2.140 Journal of Clinical Oncology - published online before print September 22, 2016 PMID: 3881560 Adjuvant chemotherapy of breast cancer: a promising experiment or standard practice? I C HendersonxI C HendersonSearch for articles by this author https://doi.org/10.1200/JCO.1985.3.2.140 First Page PDF © 1985 by American Society of Clinical Oncology
Whole-Exome Sequencing in Familial Parkinson Disease
Authors: Janice L. Farlow, Laurie A. Robak, Kurt Hetrick, Kevin Bowling, Eric Boerwinkle, Zeynep H. Coban-Akdemir, Tomasz Gambin, Richard A. Gibbs, Shen Gu, Preti Jain, Joseph Jankovic, Shalini Jhangiani, Kaveeta Kaw, Dongbing Lai, Hai Lin, Hua Ling, Yunlong Liu, James R. Lupski, Donna Muzny, Paula Porter, Elizabeth Pugh, Janson White, Kimberly Doheny, Richard M. Myers, Joshua M. Shulman, Tatiana Foroud
Journal: JAMA Neurology (2015)

Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors.