gebhart/patrepeval huggingface dataset:
Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma (2004)

Folate metabolism plays an essential role in DNA synthesis and methylation processes. Deviations in the flux of folate due to genetic variation could result in selective growth and genomic instability and affect susceptibility to various cancers including lymphoma. To test this hypothesis, genetic polymorphisms in the folate metabolic pathway were investigated using DNA from a population-based case-control study of non-Hodgkin lymphoma (NHL) conducted in the San Francisco Bay Area between 1988 and 1995. The polymorphisms examined and haplotypes generated included thymidylate synthase (TYMS 28-bp triple repeat [3R]-->double repeat [2R], 1494del6, IVS6 -68C>T, 1122A>G, and 1053C>T); 5,10-methylenetetrahydrofolate reductase (MTHFR 677C>T and 1298A>C); serine hydroxymethyltransferase (SHMT1 C1420T); reduced folate carrier (RFC G80A); and methionine synthase (MTR A2756G), making the present study the largest and most comprehensive to date to evaluate associations between genetic polymorphisms in folatemetabolizing genes and NHL risk. The TYMS 6 base pair (bp)(-)6bp- (homozygous for 6bp deletion), IVS6 -68C>T, and 1053C>T genotypes (all in complete linkage disequilibrium) were all inversely associated with NHL (TYMS; odds ratio [OR] = 0.57; 0.34-0.94), particularly with diffuse large cell lymphoma (DLCL; OR = 0.29; 0.10-0.82). Further, the MTR 2756AG/GG and the MTHFR 677TT genotypes were associated with increased risk for NHL (OR = 1.3; 0.99-1.7) and follicular lymphoma (FL; OR = 1.8; 0.98-3.1), respectively. We did not observe any significant differences in genotype frequencies of the SHMT1 and RFC polymorphisms between the cases and controls. The associations of DLCL and FL with TYMS 1494del6 and MTHFR 677TT genotypes, respectively, suggest that folate metabolism may play an important role in the pathogenesis of specific subtypes of NHL.
Physical Trauma and Tungsten Toxicity Reduce the Efficiency of Biolistic Transformation (1992)

A cell suspension culture of tobacco (Nicotiana tabacum L.) was used as a model to study injury to cells during biolistic transformation. Lawns of cells were bombarded with tungsten particles that were coated with a plasmid containing the beta-glucuronidase and the neomycin phosphotransferase II genes. When a gunpowder-driven biolistic device was used, numerous transiently expressing cells were focused around the epicenter of the blast which was manifested by a hole blown in the filter paper supporting the cells. However, transformed cells nearest the blast epicenter were injured and could not be recovered as stable transformants. The injury was primarily caused by physical trauma to the cells from gas blast and acoustic shock generated by the device. Postlaunch baffles or meshes placed in the gunpowder device reduced cell injury and increased the recovery of kanamycin-resistant colonies 3.5- and 2.5-fold, respectively. A newly developed helium-driven device was more gentle to the cells and also increased the number of transformants. Cell injury could be further moderated by using a mesh and a prelaunch baffle in the helium device. Toxicity of the tungsten microprojectiles also contributed to cell injury. Gold microprojectiles were not toxic and resulted in fourfold more kanamycin-resistant colonies than when similar quantities of similarly sized tungsten particles were used.
Role of protease-activated receptors in inflammatory responses, innate and adaptive immunity (2008)

Serine proteases are well known as enzymes involved in digestion of dietary proteins, blood coagulation, and homeostasis. Only recent groundbreaking studies revealed a novel role of serine proteases as signaling molecules acting via protease-activated receptors (PARs). Important effects of PAR activation on leukocyte motility, cytokine production, adhesion molecule expression, and a variety of other physiological or pathophysiological functions have been described in vitro and in vivo. The crucial role of PAR activation during disease progression was revealed in animal models of different gastrointestinal pathologies, neuroinflammatory and neurodegenerative processes, skin, joint and airway inflammation, or allergic responses. This review focuses on the findings related to the impact of PAR deficiency in animal models of inflammatory and allergic diseases. Additionally, we observe the role of PAR activation in the regulation of functional responses of innate and adaptive immune cells in vitro. Understanding the mechanisms by which PARs exert the effects of serine proteases on immune cells may lead to new therapeutic strategies in inflammation, immune defense, and allergy.
New insights into the pathogenesis of asthma (2003)

Asthma is a disease whose ability to cause episodic symptomatology has been appreciated since antiquity. Although the fine points of the definition can be debated, it is reasonable to think of asthma as a pulmonary disorder characterized by the generalized reversible obstruction of airflow and to define reversibility as a greater than 12% increase in the patient's forced expiratory volume in 1 second (FEV 1 ) that occurs either spontaneously or with therapy. Airway hyperresponsiveness, an exaggerated bronchospastic response to nonspecific agents such as methacholine and histamine or specific antigens, is the physiologic cornerstone of this disorder. A diagnosis of asthma is established based on a history of recurrent wheeze, cough, or shortness of breath, reversible airway obstruction demonstrated by pulmonary-function testing, and, in cases where questions exist, a methacholine challenge demonstrating airway hyperresponsiveness. It has long been assumed that patients with asthma experience intermittent attacks and have relatively normal lung function during intervening periods. More recent studies have demonstrated that asthma can cause progressive lung impairment and, in some patients, eventuate in partially reversible or irreversible airway obstruction.
High-Throughput MALDI-TOF Discovery of Genomic Sequence Polymorphisms (2004)

We describe a comparative sequencing strategy that is based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analyses of complete base-specific cleavage reactions of a target sequence. The target is converted to a DNA/RNA mosaic structure after PCR amplification using in vitro transcription. Cleavage with defined specificity is achieved by ribonucleases. The set of cleavage products is subjected to mass spectrometry without prior fractionation. The presented resequencing assay is particularly useful for single-nucleotide polymorphism (SNP) discovery. The combination of mass spectra from four complementary cleavage reactions detects approximately 98% of all possible homozygous and heterozygous SNPs in target sequences with a length of up to 500 bases. In general, both the identity and location of the sequence variation are determined. This was exemplified by the discovery of SNPs in the human gene coding for the cholesteryl ester transfer protein using a panel of 96 genomic DNAs.
MIC-1/GDF15 in Barrett’s oesophagus and oesophageal adenocarcinoma (2015)

Plasma and tissue levels of MIC-1/GDF15 are significantly elevated in patients with BO, LGD and OAC. Plasma MIC-1/GDF15 may have value in diagnosis and monitoring of Barrett's disease.
Combination of Anastrozole with Fulvestrant in the Intratumoral Aromatase Xenograft Model (2008)

Although the aromatase inhibitor anastrozole has been shown to be very effective in the treatment of hormone-dependent postmenopausal breast cancer, some patients with advanced disease will develop resistance to treatment. To investigate therapeutic strategies to overcome resistance to anastrozole treatment, we have used an intratumoral aromatase model that simulates postmenopausal breast cancer patients with estrogen-dependent tumors. Growth of the tumors in the mice was inhibited by both anastrozole and fulvestrant compared with the control tumors. Nevertheless, tumors had doubled in size at 5 weeks of treatment. We therefore investigated whether switching the original treatments to anastrozole or fulvestrant alone or the combination of anastrozole plus fulvestrant would reduce tumor growth. The results showed that the best strategy to reverse the insensitivity to anastrozole or fulvestrant is to combine the two agents. Additionally, the tumors treated with anastrozole plus fulvestrant from the beginning had only just doubled their size after 14 weeks of treatment, whereas the anastrozole and fulvestrant treatments alone resulted in 9- and 12-fold increases in tumor size, respectively, in the same time period. Anastrozole plus fulvestrant from the beginning or in sequence was associated with down-regulation of signaling proteins involved in the development of hormonal resistance such as insulin-like growth factor type I receptor beta, mitogen-activated protein kinase (MAPK), p-MAPK, AKT, mammalian target of rapamycin (mTOR), p-mTOR, and estrogen receptor alpha compared with tumors treated with anastrozole or fulvestrant alone. These results suggest that blocking the estrogen receptor and aromatase may delay or reverse the development of resistance to aromatase inhibitors in advanced breast cancer patients.
Advanced Viscoelastic Surfactant Gels for High-Density Completion Brines (2011)

Abstract Viscoelastic surfactant (VES) systems are often used as viscosifiers for solids-free, high-viscosity pills used to control brine losses in production zones after perforation, gravel packing, or frac packs due to their non-damaging characteristics. Polymer gels have relatively higher rock retention values and often damage the invaded zone, so that acidization is required for removal. The VES systems behave as "equilibrium" or "living" polymers and their viscosity can be destroyed by contact with the produced hydrocarbons or with an internal breaker. This can eliminate the need for remedial treatments, greatly reducing operating cost/time and damage to the formation. Historically, many VES systems have demonstrated limitations in high-density brines. Electrostatic screening generally reduces the viscosity or causes phase separation. Two methods have been found to stabilize VES packages in high-density completion brines: 1) by controlling the curvature of surfactant aggregates using low molecular weight surfactant polymers, nanometer scale manipulation of the phase behavior is achieved; and 2) VES gels have been developed using a mixture of oppositely charged surfactants to create gels in these high-density brines. By varying the ratios of surfactants it is possible to control micellar growth and the gel-like behavior. The interactions between the surfactants makes it possible to control the curvature and self-assembly on a nanometer scale, allowing the creation of polymer-like VES systems. The result is a greater variety of surfactants available to create gels in high-density completion brines. This paper details the laboratory work performed to develop VES packages for fluids ranging from freshwater to high-density completion brines. Extensive rheology experiments on several fluids show the viscoelasticity of these systems. The self-breaking nature of VES systems when in contact with hydrocarbons or exposed to a built-in breaker has also been demonstrated.
Nrf2 Defends the Lung from Oxidative Stress (2006)

Nuclear factor, erythroid 2 related factor 2 (Nrf2) belongs to the Cap'n'collar/basic region leucine zipper (CNC-bZIP) transcription factor family, and is activated by diverse oxidants, pro-oxidants, antioxidants, and chemopreventive agents. After phosphorylation and dissociation from the cytoplasmic inhibitor, Kelch-like ECH-associated protein 1 (Keap1), Nrf2 translocates to the nucleus and binds to an antioxidant response element (ARE). Through transcriptional induction of ARE-bearing genes that encode antioxidant-detoxifying proteins, Nrf2 activates cellular rescue pathways against oxidative injury, inflammation/immunity, apoptosis, and carcinogenesis. ARE-driven genes include direct antioxidants (e.g., GPx), thiol metabolism-associated detoxifying enzymes (e.g., GSTs), stress-response genes (e.g., HO-1), and others (e.g., PSMB5). Application of nrf2 germ-line mutant mice elucidated protective roles for Nrf2 in various models of human disorders in the liver, lung, kidney, brain, and circulation. In the lung, deficiency of nrf2 augmented injury caused by bleomycin and environmental oxidants including hyperoxia, diesel exhaust particles, and cigarette smoke. Microarray analyses of lungs from nrf2-deficient and -sufficient mice identified Nrf2-dependent genes that might be critical in pulmonary protection. Observations from these studies highlight the importance of the Nrf2-antioxidant pathway and may provide new therapeutic strategies for acute respiratory distress syndrome, idiopathic pulmonary fibrosis, cancer, and emphysema in which oxidative stress is implicated. Antioxid. Redox Signal. 8, 76–87.
FastTree: Computing Large Minimum Evolution Trees with Profiles instead of a Distance Matrix (2009)

Gene families are growing rapidly, but standard methods for inferring phylogenies do not scale to alignments with over 10,000 sequences. We present FastTree, a method for constructing large phylogenies and for estimating their reliability. Instead of storing a distance matrix, FastTree stores sequence profiles of internal nodes in the tree. FastTree uses these profiles to implement Neighbor-Joining and uses heuristics to quickly identify candidate joins. FastTree then uses nearest neighbor interchanges to reduce the length of the tree. For an alignment with N sequences, L sites, and a different characters, a distance matrix requires O(N(2)) space and O(N(2)L) time, but FastTree requires just O(NLa + N ) memory and O(N log (N)La) time. To estimate the tree's reliability, FastTree uses local bootstrapping, which gives another 100-fold speedup over a distance matrix. For example, FastTree computed a tree and support values for 158,022 distinct 16S ribosomal RNAs in 17 h and 2.4 GB of memory. Just computing pairwise Jukes-Cantor distances and storing them, without inferring a tree or bootstrapping, would require 17 h and 50 GB of memory. In simulations, FastTree was slightly more accurate than Neighbor-Joining, BIONJ, or FastME; on genuine alignments, FastTree's topologies had higher likelihoods. FastTree is available at http://microbesonline.org/fasttree.
Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon β (2004)

Identifying effective treatment combinations for MS patients failing standard therapy is an important goal. We report the results of a phase II open label baseline-to-treatment trial of a humanized monoclonal antibody against CD25 (daclizumab) in 10 multiple sclerosis patients with incomplete response to IFN-beta therapy and high brain inflammatory and clinical disease activity. Daclizumab was very well tolerated and led to a 78% reduction in new contrast-enhancing lesions and to a significant improvement in several clinical outcome measures.
I nterleukin -10 and R elated C ytokines and R eceptors (2004)

The Class 2 alpha-helical cytokines consist of interleukin-10 (IL-10), IL-19, IL-20, IL-22, IL-24 (Mda-7), and IL-26, interferons (IFN-alpha, -beta, -epsilon, -kappa, -omega, -delta, -tau, and -gamma) and interferon-like molecules (limitin, IL-28A, IL-28B, and IL-29). The interaction of these cytokines with their specific receptor molecules initiates a broad and varied array of signals that induce cellular antiviral states, modulate inflammatory responses, inhibit or stimulate cell growth, produce or inhibit apoptosis, and affect many immune mechanisms. The information derived from crystal structures and molecular evolution has led to progress in the analysis of the molecular mechanisms initiating their biological activities. These cytokines have significant roles in a variety of pathophysiological processes as well as in regulation of the immune system. Further investigation of these critical intercellular signaling molecules will provide important information to enable these proteins to be used more extensively in therapy for a variety of diseases.
Age‐associated Changes in the Skin (1982)

Like all organ systems, the skin manifests an age-associated loss of functional capacity and increasing vulnerability to injury and certain disease states. Knowledge of the aging changes in normal skin assists the physician in diagnosis and management of certain dermatoses. Awareness of the important interactions between aging skin and the environment could lead to prevention of many disorders. The burden of skin disease for the elderly is often underestimated. It is psychosocial as well as medical, and although mortality is low, morbidity is high. A rational and caring approach by the general practitioners, family physicians, internists, and geriatricians responsible for this patient population should greatly improve the situation.
Unlocking the molecular archive: the emerging use of formalin‐fixed paraffin‐embedded tissue for biomarker research in urological cancer (2009)

Rapid developments have been made in identifying predictive and prognostic markers in urological cancers. Most biomarker profiling has been primarily conducted in fresh-frozen tissue taken at the time of diagnosis or surgery. The disadvantage of this process is that the sampled tissue might not be entirely representative of the tumour and there is a lack of adequate numbers and follow-up to make clear conclusions as to a biomarker's prognostic potential. Formalin fixation and paraffin embedding (FFPE) is the clinical standard for preparing samples for histopathological assessment; this preserves tissue architecture and allows the storage of diagnostic and surplus tissue in archival banks. This resource represents a vast repository of tissue material with a long-term clinical follow-up. With the advent of high-throughput profiling technologies, there is a unique opportunity to screen and comprehensively evaluate many biomarkers. Such studies require the large sample numbers and outcome data which is a key feature of archival FFPE tissue. However, the process of FFPE induces chemical changes and degradation in tissue DNA, RNA and protein, which can make subsequent analysis unreliable. Recently, several technical advances have been made to overcome the degrading effects of FFPE. This review highlights the key advances that are beginning to allow the use of FFPE archives for molecular biomarker profiling.
HSulf-1 Inhibits Angiogenesis and Tumorigenesis In vivo (2006)

We previously identified HSulf-1 as a down-regulated gene in several tumor types including ovarian, breast, and hepatocellular carcinomas. Loss of HSulf-1, which selectively removes 6-O-sulfate from heparan sulfate, up-regulates heparin-binding growth factor signaling and confers resistance to chemotherapy-induced apoptosis. Here we report that HSulf-1 expression in MDA-MB-468 breast carcinoma clonal lines leads to reduced proliferation in vitro and reduced tumor burden in athymic nude mice in vivo. Additionally, xenografts derived from HSulf-1-expressing stable clones of carcinoma cells showed reduced vessel density, marked necrosis, and apoptosis, indicative of inhibition of angiogenesis. Consistent with this observation, HSulf-1-expressing clonal lines showed reduced staining with the endothelial marker CD31 in Matrigel plug assay, indicating that HSulf-1 expression inhibits angiogenesis. More importantly, HSulf-1 expression in the xenografts was associated with a reduced ability of vascular endothelial cell heparan sulfate to participate in a complex with fibroblast growth factor 2 (FGF-2) and its receptor tyrosine kinase FGF receptor 1c. In vitro, short hairpin RNA-mediated down-regulation of HSulf-1 in human umbilical vein endothelial cells (HUVEC) resulted in an increased proliferation mediated by heparan sulfate-dependent FGF-2, hepatocyte growth factor, and vascular endothelial growth factor 165 (VEGF165) but not by heparan sulfate-independent VEGF121. HSulf-1 down-regulation also enhanced downstream signaling through the extracellular signal-regulated kinase pathway compared with untreated cells. Consistent with the role of heparan sulfate glycosaminoglycan sulfation in VEGF-mediated signaling, treatment of HUVEC cells with chlorate, which inhibits heparan sulfate glycosaminoglycan sulfation and therefore mimics HSulf-1 overexpression, led to an attenuated VEGF-mediated signaling. Collectively, these observations provide the first evidence of a novel mechanism by which HSulf-1 modulates the function of heparan sulfate binding VEGF165 in proliferation and angiogenesis.
The Molecular Basis of Turcot's Syndrome (1995)

The association between brain tumors and multiple colorectal adenomas can result from two distinct types of germ-line defects: mutation of the APC gene or mutation of a mismatch-repair gene. Molecular diagnosis may contribute to the appropriate care of affected patients.
Selective Induction of Colon Cancer Cell Apoptosis by 5-Fluorouracil in Humans (2002)

To assess the mechanism of action of 5-fluorouracil (5-FU) apoptosis (AI) and proliferation (PI) indices were determined histochemically in colon carcinoma and normal colon tissue of 7 patients treated preoperatively with 5-FU (300 mg/m2/day for 5 days) and 11 controls. 5-Fluorouracil induced apoptosis selectively in malignant colonocytes (AI in 5-FU-group: 0.126 +/- 0.016 [mean +/- SEM] vs. 0.065 +/- 0.012 in controls; P < 0.05), but not in normal colonocytes. 5-Fluorouracil had no effect on the PI of either normal or malignant colonocytes. 5-Fluorouracil-induced apoptosis did not correlate with clinical outcome at 24 months. We conclude that 5-FU: (a) induces apoptosis selectively in colon cancer cells, while it spares the normal colonic mucosa, and (b) has no effect on colonocyte proliferation under the conditions of our protocol. This effect of 5-FU may contribute to its chemotherapeutic activity in human colon cancer.
Safety and Survival With GVAX Pancreas Prime and Listeria Monocytogenes–Expressing Mesothelin (CRS-207) Boost Vaccines for Metastatic Pancreatic Cancer (2015)

Heterologous prime/boost with Cy/GVAX and CRS-207 extended survival for patients with pancreatic cancer, with minimal toxicity.