tbuckley/cabot-search huggingface dataset:
Quantifying the Stationarity and Time Reversibility of the Nucleotide Substitution Process
Authors: F. Squartini, P. F. Arndt
Journal: Molecular Biology and Evolution (2008)

Markov models describing the evolution of the nucleotide substitution process, widely used in phylogeny reconstruction, usually assume the hypotheses of stationarity and time reversibility. Although these models give meaningful results when applied to biological data, it is not clear if the 2 assumptions mentioned above hold and, if not, how much sequence evolution processes deviate from them. To this aim, we introduce 2 sets of indices that can be calculated from the nucleotide distribution and the substitution rates. The stationarity indices (STIs) can be used to test the validity of the equilibrium assumption. The irreversibility indices (IRIs) are derived from the Kolmogorov cycle conditions for time reversibility and quantify the degree of nontime reversibility of a process. We have computed STIs and IRIs for the evolutionary process of 2 lineages, Drosophila simulans and Homo sapiens. In the latter case, we use a modified form of the indices that takes into account the CpG decay process. In both cases, we find statistically significant deviations from the ideal case of a process that has reached stationarity and is time reversible.
Substitution Rate and Structural Divergence of 5′UTR Evolution: Comparative Analysis Between Human and Cynomolgus Monkey cDNAs
Authors: Naoki Osada, Makoto Hirata, Reiko Tanuma, Jun Kusuda, Munetomo Hida, Yutaka Suzuki, Sumio Sugano, Takashi Gojobori, C.-K. James Shen, Chung-I Wu, Katsuyuki Hashimoto
Journal: Molecular Biology and Evolution (2005)

The substitution rate and structural divergence in the 5′-untranslated region (UTR) were investigated by using human and cynomolgus monkey cDNA sequences. Due to the weaker functional constraint in the UTR than in the coding sequence, the divergence between humans and macaques would provide a good estimate of the nucleotide substitution rate and structural divergence in the 5′UTR. We found that the substitution rate in the 5′UTR (K5UTR) averaged ≈10%–20% lower than the synonymous substitution rate (Ks). However, both the K5UTR and nonsynonymous substitution rate (Ka) were significantly higher in the testicular cDNAs than in the brain cDNAs, whereas the Ks did not differ. Further, an in silico analysis revealed that 27% (169/622) of macaque testicular cDNAs had an altered exon-intron structure in the 5′UTR compared with the human cDNAs. The fraction of cDNAs with an exon alteration was significantly higher in the testicular cDNAs than in the brain cDNAs. We confirmed by using reverse transcriptase–polymerase chain reaction that about one-third (6/16) of in silico “macaque–specific” exons in the 5′UTR were actually macaque specific in the testis. The results imply that positive selection increased K5UTR and structural alteration rate of a certain fraction of genes as well as Ka. We found that both positive and negative selection can act on the 5′UTR sequences.
Pregnancy Outcome Following Maternal Use of the New Selective Serotonin Reuptake Inhibitors
Authors: Nathalie A. Kulin, Anne Pastuszak, Suzanne R. Sage, Betsy Schick-Boschetto, Glenda Spivey, Marcia Feldkamp, Kelly Ormond, Doreen Matsui, Amy K. Stein-Schechman, Lola Cook, Joanne Brochu, Michael Rieder, Gideon Koren
Journal: JAMA (1998)

Context.-Although a large number of women of reproductive age use new selective serotonin reuptake inhibitors (SSRIs) and half of all pregnancies are unplanned, no data exist on the safety of these agents for the human fetus.Objective.-Toassess fetal safety and risk of fluvoxamine, paroxetine, and sertraline.Design.-A prospective, multicenter, controlled cohort study.Setting.-Nine Teratology Information Service centers in the United States and Canada.Patients.-Allwomen who were counseled during pregnancy following exposure to a new SSRI and followed up by the participating centers.Controls were randomly selected from women counseled after exposure to nonteratogenic agents.Main Outcome Measures.-Rates of major congenital malformations.Results.-A total of 267 women exposed to an SSRI and 267 controls were studied.Exposure to SSRIs was not associated with either increased risk for major malformations (9/222 live births [4.1%] vs 9/235 live births [3.8%] in the controls, relative risk, 1.06, 95% confidence interval, 0.43-2.62)or higher rates of miscarriage, stillbirth, or prematurity.Mean (SD) birth weights among SSRI users (3439 [505] g) were similar to the controls (3445 [610] g) as were the gestational ages (39.4 [1.7] weeks vs 39.4 [1.9] weeks).Conclusion.-The new SSRIs, fluvoxamine, paroxetine, and sertraline, do not appear to increase the teratogenic risk when used in their recommended doses.
Integrative and Comparative Genomic Analysis of Lung Squamous Cell Carcinomas in East Asian Patients
Authors: Youngwook Kim, Peter S. Hammerman, Jaegil Kim, Ji-ae Yoon, Yoomi Lee, Jong-Mu Sun, Matthew D. Wilkerson, Chandra Sekhar Pedamallu, Kristian Cibulskis, Yeong Kyung Yoo, Michael S. Lawrence, Petar Stojanov, Scott L. Carter, Aaron McKenna, Chip Stewart, Andrey Y. Sivachenko, In-Jae Oh, Hong Kwan Kim, Yong Soo Choi, Kwhanmien Kim, Young Mog Shim, Kyu-Sik Kim, Sang-Yun Song, Kook-Joo Na, Yoon-La Choi, D. Neil Hayes, Jhingook Kim, Sukki Cho, Young-Chul Kim, Jin Seok Ahn, Myung-Ju Ahn, Gad Getz, Matthew Meyerson, Keunchil Park
Journal: Journal of Clinical Oncology (2013)

Purpose Lung squamous cell carcinoma (SCC) is the second most prevalent type of lung cancer. Currently, no targeted therapeutics are approved for treatment of this cancer, largely because of a lack of systematic understanding of the molecular pathogenesis of the disease. To identify therapeutic targets and perform comparative analyses of lung SCC, we probed somatic genome alterations of lung SCC by using samples from Korean patients. Patients and Methods We performed whole-exome sequencing of DNA from 104 lung SCC samples from Korean patients and matched normal DNA. In addition, copy-number analysis and transcriptome analysis were conducted for a subset of these samples. Clinical association with cancer-specific somatic alterations was investigated. Results This cancer cohort is characterized by a high mutational burden with an average of 261 somatic exonic mutations per tumor and a mutational spectrum showing a signature of exposure to cigarette smoke. Seven genes demonstrated statistical enrichment for mutation: TP53, RB1, PTEN, NFE2L2, KEAP1, MLL2, and PIK3CA). Comparative analysis between Korean and North American lung SCC samples demonstrated a similar spectrum of alterations in these two populations in contrast to the differences seen in lung adenocarcinoma. We also uncovered recurrent occurrence of therapeutically actionable FGFR3-TACC3 fusion in lung SCC. Conclusion These findings provide new steps toward the identification of genomic target candidates for precision medicine in lung SCC, a disease with significant unmet medical needs.
Budesonide and formoterol inhibit ICAM-1 and VCAM-1 expression of human lung fibroblasts
Authors: FM Spoelstra, DS Postma, H Hovenga, JA Noordhoek, HF Kauffman
Journal: European Respiratory Journal (2000)

The glucocorticoid budesonide and the long-acting beta2-adrenoceptor agonist formoterol are used in asthma therapy for their anti-inflammatory and bronchodilating effects, respectively. Since expression of adhesion molecules on resident cells in the lung plays an important role in asthmatic inflammatory responses, the effects of these drugs on the cytokine-induced intercellular adhesion molecule-1 (ICAM)-1 and vascular cell adhesion molecule-1 (VCAM)-1 expression of human lung fibroblasts were investigated. Budesonide and formoterol were added in the absence or presence of interleukin (IL)-1beta, tumour necrosis factor-alpha (TNF-alpha), interferon gamma (IFN-gamma) or IL-4 to human lung fibroblasts; ICAM-1 and VCAM-1 expression were measured after 8 h using a cell surface enzyme linked immunosorbent assay (ELISA). It was found that both budesonide and formoterol significantly inhibited (p&lt;0.05) the increased expression of ICAM-1 and VCAM-1 after stimulation with IL-1beta (maximal inhibition (median (25-75% percentiles) 50 (48-52) and 61% (42-69), respectively, with budesonide and 55 (50-73) and 86% (64-94), respectively, with formoterol (10(-7) M)), TNF-alpha (maximal inhibition 49 (46-57) and 57% (44-68), respectively, with budesonide and 44 (40-75) and 62% (52-83) respectively, with formoterol), IFN-gamma (maximal inhibition 64% (41-67) with budesonide and 39% (29-49) with formoterol for ICAM-1) and IL-4 (maximal inhibition 82% (69-92) with budesonide and 43% (33-67) with formoterol for VCAM-1) in a dose-dependent manner. The results show that budesonide, as well as formoterol, in probably clinically relevant concentrations inhibits cytokine-induced adhesion molecule expression on human lung fibroblasts from a concentration of 10(-9) M. This inhibitory effect on resident cells may have implications for the infiltration of inflammatory cells into pulmonary tissue during therapy with these drugs in asthma.
Laboratory Creation of a Highly Transmissible H5N1 Influenza Virus: Balancing Substantial Risks and Real Benefits
Authors: Andrew T. Pavia
Journal: Annals of Internal Medicine (2012)

Controversy erupted when influenza researchers announced that they had created an H5N1 influenza virus that was transmissible between ferrets. The controversy escalated when the National Science Advisory Board for Biosecurity (NSABB) recommended that the work be published but recommended significant voluntary redactions. The responses to the NSABB action and to the research itself have been polarized. A readily transmitted H5N1 virus could be extraordinarily lethal; therefore, the risk for accidental release is significant, and deliberate misuse of the data to create a biological weapon is possible. However, the knowledge gained by these and future experiments under appropriate safeguards is likely to allow critical understanding of influenza transmission and virulence. It would be irresponsible to adopt either extreme solution: to prevent and censor the research or to allow unlimited distribution without careful review by an independent group, such as the NSABB.
TLR2/6 agonists and IFNγ synergize to induce melanoma cells to produce T-cell recruiting chemokines
Authors: Ileana S Mauldin, Ena Wang, Donna H Deacon, Craig L Slingluff
Journal: Journal for ImmunoTherapy of Cancer (2013)

Meeting abstracts Melanoma is currently the most lethal form of skin cancer. Clinical efforts to combat melanoma have included approaches to induce the immune system, through T-cell directed therapies, to clear melanoma. These approaches require that immune cells enter the tumor microenvironment to
J. SKINNER Body Energy
Authors: H. E. Robson
Journal: British Journal of Sports Medicine (1982)

listened to an Advent Mass in Manila Cathedral, walked round the old Fort Santiago, badly damaged during the recapture of Manila in 1945, and walked home through the magnificent Rizal Park, past the memorial to the liberator executed on that spot, and guarded 24 hours a day.A half-day trip to a volcano lying in a crater lake in a larger volcano, started off badly when the minibus broke down, but we got there eventually.Another full day trip was to a fast-running river, ascended laboriously by canoe, but with a rapid return journey down the rapids.A double capsize in the flooded river prevented us getting all the way up to a waterfall, but we arrived back at our base very wet, including the cameras.Apart from these trips, we received hospitality at lunch from Dr. Macaraeg, Secretary of the Philippines Sports Medicine Association, and his wife, from Dr. Leonard Gilbert, an American who is one of the very few permitted to work in the Philippines, and by the President of the Philippines Sports Medicine Association, Dr.
Not Working 3 Years After Breast Cancer: Predictors in a Population-Based Study
Authors: Mélanie Drolet, Elizabeth Maunsell, Jacques Brisson, Chantal Brisson, Benoît Mâsse, Luc Deschênes
Journal: Journal of Clinical Oncology (2005)

Purpose Little is known about factors increasing likelihood of not working among breast cancer survivors compared with women in the general population. Patients and Methods A population-based retrospective cohort study was conducted in Quebec, Canada, based on the consecutive series of working women aged younger than 60 years when first treated for breast cancer (identified through the Quebec Tumor Registry), and on a group of randomly selected similar women, living in Quebec, who were working at the time of survivors' diagnoses, but who were without cancer (identified through provincial health care files). Data came from a telephone interview, 3 years after diagnosis for 646 survivors (73% of those eligible) or during a similar period for 890 comparison women (51%). Results Slightly more survivors were not working 3 years after diagnosis compared with women never diagnosed with cancer (21% and 15%, respectively). Older age (for survivors and comparison women, relative risk [RR] = 4.62, P &lt; .0001 and RR = 4.98, P &lt; .0001, respectively) and union membership (RR = 1.88, P = .0003 and RR = 1.40, P = .06, respectively) increased the likelihood of not working at the end of follow-up. In addition, income less than $20,000 compared with ≥ $50,000 was associated with not working only among survivors (RR = 3.18; P = .0008). Adjuvant treatments did not predict work cessation, but any new cancer event during follow-up did (RR = 2.14; P &lt; .0001). Conclusion Although reassuring that adjuvant treatments did not appear to play a role in survivors' not working, other aspects of the cancer experience might nonetheless have influenced the decision to reduce work effort after breast cancer.
Identification of a new disease cluster of pemphigus vulgaris with autoimmune thyroid disease, rheumatoid arthritis and type I diabetes
Authors: A. Parameswaran, K. Attwood, R. Sato, K. Seiffert-Sinha, A.A. Sinha
Journal: British Journal of Dermatology (2014)

Pemphigus vulgaris (PV) is a potentially fatal autoimmune blistering skin disease. It is known that individuals with autoimmune diseases such as PV, as well as their family members, are at increased risk of developing other autoimmune diseases. However, it is unknown whether there are specific autoimmune diseases that cluster with PV.To investigate the frequency of coexisting autoimmune diseases in patients with PV and their relatives, to determine the prevalence of specific autoimmune diseases in patients with PV vs. the general population and to identify statistically significant clinical clusters linking PV with other autoimmune disorders.We performed a cross-sectional study and meta-analysis of patient data from our own patient database (n = 230), an anonymous online survey conducted by our laboratory (n = 171) and the International Pemphigus & Pemphigoid Foundation registry (n = 393).We found that the prevalences of autoimmune thyroid disease (AITD), rheumatoid arthritis and type 1 diabetes were significantly increased in patients with PV compared with the general population. These diseases were also among the most frequent in family members of patients with PV, in addition to systemic lupus erythematosus (SLE). Descriptive cluster analysis using basic principle components methods revealed that PV forms a distinct cluster with AITD, rheumatoid arthritis and type 1 diabetes, and another cluster with SLE, AITD and rheumatoid arthritis.PV belongs to an established autoimmune disease cluster that includes AITD, rheumatoid arthritis and type 1 diabetes. Our data suggest the possibility of common genetic elements across clinically distinct diseases that might underlie autoimmune susceptibility.
Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver
Authors: Shu-hao Hsu, Bo Wang, Janaiah Kota, Jianhua Yu, Stefan Costinean, Huban Kutay, Lianbo Yu, Shoumei Bai, Krista La Perle, Raghu R. Chivukula, Hsiaoyin Mao, Min Wei, K. Reed Clark, Jerry R. Mendell, Michael A. Caligiuri, Samson T. Jacob, Joshua T. Mendell, Kalpana Ghoshal
Journal: Journal of Clinical Investigation (2012)

miR-122, an abundant liver-specific microRNA (miRNA), regulates cholesterol metabolism and promotes hepatitis C virus (HCV) replication. Reduced miR-122 expression in hepatocellular carcinoma (HCC) correlates with metastasis and poor prognosis. Nevertheless, the consequences of sustained loss of function of miR-122 in vivo have not been determined. Here, we demonstrate that deletion of mouse Mir122 resulted in hepatosteatosis, hepatitis, and the development of tumors resembling HCC. These pathologic manifestations were associated with hyperactivity of oncogenic pathways and hepatic infiltration of inflammatory cells that produce pro-tumorigenic cytokines, including IL-6 and TNF. Moreover, delivery of miR-122 to a MYC-driven mouse model of HCC strongly inhibited tumorigenesis, further supporting the tumor suppressor activity of this miRNA. These findings reveal critical functions for miR-122 in the maintenance of liver homeostasis and have important therapeutic implications, including the potential utility of miR-122 delivery for selected patients with HCC and the need for careful monitoring of patients receiving miR-122 inhibition therapy for HCV.
Bortezomib suppresses function and survival of plasmacytoid dendritic cells by targeting intracellular trafficking of Toll-like receptors and endoplasmic reticulum homeostasis
Authors: Makiko Hirai, Norimitsu Kadowaki, Toshio Kitawaki, Haruyuki Fujita, Akifumi Takaori-Kondo, Ryutaro Fukui, Kensuke Miyake, Takahiro Maeda, Shimeru Kamihira, Yoshiki Miyachi, Takashi Uchiyama
Journal: Blood (2010)
Transient Limb Ischemia Induces Remote Ischemic Preconditioning In Vivo
Authors: R.K. Kharbanda, U.M. Mortensen, P.A. White, S.B. Kristiansen, M.R. Schmidt, J.A. Hoschtitzky, M. Vogel, K. Sorensen, A.N. Redington, R. MacAllister
Journal: Circulation (2002)

Background— Ischemic preconditioning reduces local tissue injury caused by subsequent ischemia-reperfusion (IR), but may also have a salutary effect on IR injury of tissues remote from those undergoing preconditioning. We tested the hypothesis that limb ischemia induces remote preconditioning, reduces endothelial IR injury in humans, and reduces experimental myocardial infarct size. Methods and Results— Endothelial IR injury of the human forearm was induced by 20 minutes of upper limb ischemia (inflation of a blood pressure cuff to 200 mm Hg) followed by reperfusion. Remote preconditioning was induced by three 5-minute cycles of ischemia of the contralateral limb. Venous occlusion plethysmography was used to assess forearm blood flow in response to acetylcholine at baseline and 15 minutes after reperfusion. Experimental myocardial infarction was achieved by 40 minutes of balloon occlusion of the left anterior descending artery in 15-kg pigs. Remote preconditioning was induced by four 5-minute cycles of lower limb ischemia. Triphenyltetrazolium staining was used to assess the extent of myocardial infarction. In the human study, the response to acetylcholine was significantly attenuated in the control group after 15 minutes’ reperfusion, but remote preconditioning prevented this reduction. Limb ischemia caused a significant reduction in the extent of myocardial infarction relative to the area at risk compared with control (26±9% versus 53±8%, P &lt;0.05). Conclusion— Remote ischemic preconditioning prevents IR-induced endothelial dysfunction in humans and reduces the extent of myocardial infarction in experimental animals. Transient limb ischemia is a simple preconditioning stimulus with important potential clinical applications.
Inosine Triphosphate Pyrophosphohydrolase (ITPA) polymorphic sequence variants in adult hematological malignancy patients and possible association with mitochondrial DNA defects
Authors: Mazin A Zamzami, John A Duley, Gareth R Price, Deon J Venter, John W Yarham, Robert W Taylor, Laurence P Catley, Timothy HJ Florin, Anthony M Marinaki, Francis Bowling
Journal: Journal of Hematology & Oncology (2013)

Abstract Background Inosine triphosphate pyrophosphohydrolase (ITPase) is a ‘house-cleaning’ enzyme that degrades non-canonical (‘rogue’) nucleotides. Complete deficiency is fatal in knockout mice, but a mutant polymorphism resulting in low enzyme activity with an accumulation of ITP and other non-canonical nucleotides, appears benign in humans. We hypothesised that reduced ITPase activity may cause acquired mitochondrial DNA (mtDNA) defects. Furthermore, we investigated whether accumulating mtDNA defects may then be a risk factor for cell transformation, in adult haematological malignancy (AHM). Methods DNA was extracted from peripheral blood and bone marrow samples. Microarray-based sequencing of mtDNA was performed on 13 AHM patients confirmed as carrying the ITPA 94C&gt;A mutation causing low ITPase activity, and 4 AHM patients with wildtype ITPA . The frequencies of ITPA 94C&gt;A and IVS2+21A&gt;C polymorphisms were studied from 85 available AHM patients. Results ITPA 94C&gt;A was associated with a significant increase in total heteroplasmic/homoplasmic mtDNA mutations (p&lt;0.009) compared with wildtype ITPA , following exclusion of haplogroup variants. This suggested that low ITPase activity may induce mitochondrial abnormalities. Compared to the normal population, frequencies for the 94C&gt;A and IVS2+21A&gt;C mutant alleles among the AHM patients were higher for myelodyplastic syndrome (MDS) - but below significance; were approximately equivalent for chronic lymphoblastic leukemia; and were lower for acute myeloid leukemia. Conclusions This study invokes a new paradigm for the evolution of MDS, where nucleotide imbalances produced by defects in ‘house-cleaning’ genes may induce mitochondrial dysfunction, compromising cell integrity. It supports recent studies which point towards an important role for ITPase in cellular surveillance of rogue nucleotides.
Successful antibiotic treatment of Helicobacter pylori negative gastric mucosa associated lymphoid tissue lymphomas
Authors: M Raderer
Journal: Gut (2005)

The role of antibiotic treatment in early stage gastric mucosa associated lymphoid tissue (MALT) lymphoma not associated with Helicobacter pylori infection has not been investigated.Six patients with localised gastric MALT lymphoma underwent antibiotic treatment with clarithromycin, metronidazole, and pantoprazole. Staging, including endosonography plus gastroscopy, computed tomography of the thorax and abdomen, colonoscopy, magnetic resonance imaging of the salivary glands, and bone marrow biopsy were performed to rule out distant spread of the disease. In addition, MALT specific genetic changes, including reverse transcriptase-polymerase chain reaction for t(11;18)(q21;q21), were tested in all patients. H pylori infection was ruled out by histology, urease breath test, serology, and stool antigen testing.All six patients had MALT lymphoma restricted to the stomach, and no evidence of infection with H pylori was found. Only one patient tested positive for t(11;18)(q21;q21) while the remaining five displayed no genetic aberrations. Following antibiotic treatment, endoscopic controls were performed every three months. Five patients responded with lymphoma regression between three and nine months following antibiotic treatment (one partial remission and four complete responses). One patient had stable disease for 12 months and was then referred for chemotherapy.Patients with early stage gastric MALT lymphoma negative for H pylori might still benefit from antibiotic treatment as the sole treatment modality.