tbuckley/cabot-search huggingface dataset:
Ecological Adaptation in Bacteria: Speciation Driven by Codon Selection
Authors: Adam C. Retchless, Jeffrey G. Lawrence
Journal: Molecular Biology and Evolution (2012)

In bacteria, physiological change may be effected by a single gene acquisition, producing ecological differentiation without genetic isolation. Natural selection acting on such differences can reduce the frequency of genotypes that arise from recombination at these loci. However, gene acquisition can only account for recombination interference in the fraction of the genome that is tightly linked to the integration site. To identify additional loci that contribute to adaptive differences, we examined orthologous genes in species of Enterobacteriaceae to identify significant differences in the degree of codon selection. Significance was assessed using the Adaptive Codon Enrichment metric, which accounts for the variation in codon usage bias that is expected to arise from mutation and drift; large differences in codon usage bias were identified in more genes than would be expected to arise from stochastic processes alone. Genes in the same operon showed parallel differences in codon usage bias, suggesting that changes in the overall levels of gene expression led to changes in the degree of adaptive codon usage. Most significant differences between orthologous operons were found among those involved with specific environmental adaptations, whereas "housekeeping" genes rarely showed significant changes. When considered together, the loci experiencing significant changes in codon selection outnumber potentially adaptive gene acquisition events. The identity of genes under strong codon selection seems to be influenced by the habitat from which the bacteria were isolated. We propose a two-stage model for how adaptation to different selective regimes can drive bacterial speciation. Initially, gene acquisitions catalyze rapid ecological differentiation, which modifies the utilization of genes, thereby changing the strength of codon selection on them. Alleles develop fitness variation by substitution, producing recombination interference at these loci in addition to those flanking acquired genes, allowing sequences to diverge across the entire genome and establishing genetic isolation (i.e., protection from frequent homologous recombination).
Tissue-specific expression of B7x protects from CD4 T cell–mediated autoimmunity
Authors: Joyce Wei, P’ng Loke, Xingxing Zang, James P. Allison
Journal: The Journal of Experimental Medicine (2011)

B7x, an inhibitory member of the B7/CD28 superfamily, is highly expressed in a broad range of nonhematopoietic organs, suggesting a role in maintaining peripheral tolerance. As endogenous B7x protein is expressed in pancreatic islets, we investigated whether the molecule inhibits diabetogenic responses. Transfer of disease-inducing BDC2.5 T cells into B7x-deficient mice resulted in a more aggressive form of diabetes than in wild-type animals. This exacerbation of disease correlated with higher frequencies of islet-infiltrating Th1 and Th17 cells. Conversely, local B7x overexpression inhibited the development of autoimmunity, as crossing diabetes-susceptible BDC2.5/B6g7 mice to animals overexpressing B7x in pancreatic islets abrogated disease induction. This protection was caused by the inhibition of IFN-γ production by CD4 T cells and not to a skewing or expansion of Th2 or regulatory T cells. The suppressive function of B7x was also supported by observations from another autoimmune model, experimental autoimmune encephalomyelitis, in which B7x-deficient mice developed exacerbated disease in comparison with wild-type animals. Analysis of central nervous system–infiltrating immune cells revealed that the loss of endogenous B7x resulted in expanded Th1 and Th17 responses. Data from these two autoimmune models provide evidence that B7x expression in the periphery acts as an immune checkpoint to prevent tissue-specific autoimmunity.
The genome and transcriptome of Haemonchus contortus, a key model parasite for drug and vaccine discovery
Authors: Roz Laing, Taisei Kikuchi, Axel Martinelli, Isheng J Tsai, Robin N Beech, Elizabeth Redman, Nancy Holroyd, David J Bartley, Helen Beasley, Collette Britton, David Curran, Eileen Devaney, Aude Gilabert, Martin Hunt, Frank Jackson, Stephanie L Johnston, Ivan Kryukov, Keyu Li, Alison A Morrison, Adam J Reid, Neil Sargison, Gary I Saunders, James D Wasmuth, Adrian Wolstenholme, Matthew Berriman, John S Gilleard, James A Cotton
Journal: Genome biology (2013)

The small ruminant parasite Haemonchus contortus is the most widely used parasitic nematode in drug discovery, vaccine development and anthelmintic resistance research. Its remarkable propensity to develop resistance threatens the viability of the sheep industry in many regions of the world and provides a cautionary example of the effect of mass drug administration to control parasitic nematodes. Its phylogenetic position makes it particularly well placed for comparison with the free-living nematode Caenorhabditis elegans and the most economically important parasites of livestock and humans.
Irisin is inversely associated with intrahepatic triglyceride contents in obese adults
Authors: Hui-Jie Zhang, Xian-Feng Zhang, Zhi-Min Ma, Ling-Ling Pan, Zheng Chen, Hai-Wei Han, Cheng-Kun Han, Xiong-Jie Zhuang, Yan Lu, Xue-Jun Li, Shu-Yu Yang, Xiao-Ying Li
Journal: Journal of Hepatology (2013)
Short-Term Pravastatin Mediates Growth Inhibition and Apoptosis, Independently of Ras, via the Signaling Proteins p27Kip1 and PI3 Kinase
Authors: ROBERT H. WEISS, AL RAMIREZ, ADRIANE JOO
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Growth factor-stimulated DNA synthesis in a variety of cell lines has been shown to be decreased after overnight (or longer) treatment with the 3-hydroxy-3-methylglutaryl CoA reductase inhibitors, the statins. Although this anti-mitogenic effect had been presumed to be the result of the impairment of Ras lipidation, a stable modification (T 1/2 approximately 20 h), this study provides new data demonstrating that brief (approximately 1 h) pretreatment of rat vascular smooth muscle cells with 100 μM pravastatin before platelet-derived growth factor-BB (PDGF-BB) stimulation results in attenuation of DNA synthesis through a Ras-independent mechanism. PDGF-BB-stimulated PDGF-β receptor tyrosine phosphorylation, Ras activity, and mitogen-activated protein/extracellular signal-regulated kinase activity are unaffected by from 10 min to 1 h of pravastatin incubation, while Raf activity is markedly increased after 1 h of pravastatin. Phosphatidylinositol-3 kinase activity and phosphorylation of its downstream effector Akt are decreased after 1 h pravastatin incubation. Rho is stabilized by pravastatin, and ADP-ribosylation of Rho by C3 exoenzyme decreases PDGF-stimulated phosphatidylinositol-3 kinase activity, mimicking the effect of pravastatin on this signaling protein. Levels of the cyclin-dependent kinase inhibitor p27 Kip 1 are increased when cells were preincubated with pravastatin for 1 h and then exposed to PDGF, and apoptosis is induced by pravastatin incubation times as short as 1 to 4 h. Thus, short-term, high-dose pravastatin inhibits vascular smooth muscle cell growth and induces apoptosis independently of Ras, likely by means of the drug's effect on p27 Kip 1 , mediated by Rho and/or phosphatidylinositol-3 kinase. This work demonstrates for the first time that the statins may be therapeutically useful when applied for short periods of time such that potential toxicity of long-term statin use (such as chronic Ras inhibition) may be avoided, suggesting future therapeutic directions for statin research.
Noninvasive Evaluation of Coronary Reperfusion by Transthoracic Doppler Echocardiography in Patients With Anterior Acute Myocardial Infarction Before Coronary Intervention
Authors: Souki Lee, Yutaka Otsuji, Shinichi Minagoe, Shuichi Hamasaki, Koichi Toyonaga, Midori Negishi, Masanori Tsurugida, Hitoshi Toda, Chuwa Tei
Journal: Circulation (2003)

Background— Transthoracic Doppler echocardiography (TTDE) enables evaluation of distal left anterior descending coronary artery (LAD) flow. The purpose of this study was to test whether TTDE can differentiate coronary reperfusion with Thrombolysis in Myocardial Infarction (TIMI) grade 3 from TIMI grade ≤2 in patients with anterior acute myocardial infarction (AMI). Methods and Results— In 46 consecutive patients with a first anterior AMI in the acute phase before emergent coronary intervention, the presence of antegrade distal LAD flow and its diastolic peak velocity were evaluated by color and pulsed TTDE and compared with TIMI grades by subsequent coronary angiography performed 29±12 minutes later. Nineteen patients had TIMI 0 reperfusion, 4 had TIMI 1, 10 had TIMI 2, and 13 had TIMI 3. Visual antegrade distal LAD flow was present in 22 of the 46 patients. TIMI 2 and 3 reperfusions were both generally visualized by color TTDE. However, peak distal LAD flow velocity by pulsed TTDE was significantly greater in patients with TIMI 3 compared with those with TIMI 2 (40±10 vs 20±6 cm/s, P &lt;0.0001). The diagnosis of TIMI 3 based on diastolic peak distal LAD flow velocity ≥25 cm/s by TTDE had a sensitivity, specificity, and accuracy of 77%, 94%, and 89%, respectively. Conclusion— TTDE enables noninvasive differentiation of TIMI 3 from TIMI ≤2 coronary reperfusion in patients with AMI in the acute phase before emergent coronary intervention.
CXCL10 plays a key role as an inflammatory mediator and a non-invasive biomarker of non-alcoholic steatohepatitis
Authors: Xiang Zhang, Jiayun Shen, Kwan Man, Eagle S.H. Chu, Tung On Yau, Joanne C.Y. Sung, Minnie Y.Y. Go, Jun Deng, Liwei Lu, Vincent W.S. Wong, Joseph J.Y. Sung, Geoffrey Farrell, Jun Yu
Journal: Journal of Hepatology (2014)
Reply to P. Stattin
Authors: Sandip M. Prasad, Jim C. Hu
Journal: Journal of Clinical Oncology (2015)

We read with interest the comments of Stattin 1 regarding our findings 2 on worse overall survival for men with depression with newly diagnosed prostate cancer.We did not identify a difference in cancer-specific survival between depressed and nondepressed men, and we agree that the contribution of non-prostate cancer death such as cardiovascular mortality in men receiving androgen-deprivation therapy 3 and increased rates of suicide in men with newly diagnosed prostate cancer may explain part of the observed difference in overall survival.However, we also believe that disparities based on preexisting depression diagnosis may influence the selection of androgendeprivation therapy as primary therapy for clinically localized prostate cancer (more common in depressed men).In addition, we elected to focus on overall survival as our primary outcome, because attribution bias and misclassification of cause of death in men with prostate cancer exist, 4 although prior validation of cause of death demonstrated excellent agreement between SEER data and medical record review ( statistic ϭ 0.91). 5This was also seen in the Goteborg randomized population-based prostate cancer screening trial, where the rate of agreement on cause of death from a death certificate and an independent cause of death committee was 96%. 6owever, there may also be discord in the classification of cause of death, even with detailed medical review.In PIVOT (Prostate Cancer Intervention Versus Observation Trial), a low level of agreement (56%) among the three members of the PIVOT End Points Committee on cause of death was seen. 7In the end, we believed that the outcome of overall survival best captured measured and unmeasured effects of prostate cancer diagnosis and treatment between depressed and nondepressed men.As noted in the final paragraph of our report, "although EM [expectant management] may be appropriate for elderly men with low-risk disease, depression may blunt the aggressiveness for intermediate-and high-risk disease." 2(p2477) We believe that the separation of the Kaplan-Meier curves 3 years after diagnosis for these two populations may reflect differences based on initial treatment selection.We agree that the early separation of these survival curves in low-risk patients may reflect non-prostate cancer deaths.We eagerly anticipate additional follow-up of these cohorts over time to determine if the trends in cancer-specific survival echo those of overall survival seen in our study.
Long‐Term Treatment with Beclomethasone Dipropionate Aerosol in Asthmatic Children, with Special Reference to Growth
Authors: Viggo Graff‐Lonnevig, Sven Kraepelien
Journal: Allergy (1979)

Thirty‐one children, 19 boys and 12 girls, aged 3.4–10.8 years, with severe perennial bronchial asthma were treated with beclomethasone dipropionate aerosol (BDA) for 16–40 months. The dose was initially 400 μg a day and was gradually reduced to the lowest level giving control of symptoms. Earlier steroid or ACTH‐treatment in six children was stopped during the BDA‐treatment. At the start of the treatment the mean deviation of height compared with normal values for Swedish children was −0.10 s.d. for the boys and −0.51 s.d. for the girls. At the end of the observation period the deviation was −0.22 s.d. and −0.58 s.d., respectively. The increase in deviation was not significant. Bone age was also slightly retarded before beclomethasone treatment but this deviation was not accentuated during the observation period. It is concluded that treatment with BDA does not retard growth or skeletal maturation in children. The number of acute admissions to hospital was reduced by more than 50% during the first year of treatment.
MET As a Possible Target for Non–Small-Cell Lung Cancer
Authors: Ahad A. Sadiq, Ravi Salgia
Journal: Journal of Clinical Oncology (2013)

Lung cancer is a heterogeneous group of disorders that is now being subdivided into molecular subtypes with dedicated targeted therapies. The MET receptor tyrosine kinase has been identified as aberrantly overexpressed, potentially having activating mutations, and amplified in certain subsets of lung cancers. The ligand hepatocyte growth factor (HGF) can also be overexpressed in lung cancer or expressed in stroma, and both the MET receptor and the HGF ligand can be targets for therapeutics, especially in lung cancer. Activation of MET leads to a plethora of biochemical and biologic changes both in normal and cancerous cells. Preclinically, it has been shown that silencing or inactivating MET leads to decreased viability of cancer cells. There are a number of compounds against MET/HGF in clinical trials that have been shown to be active in lung cancers. This review will summarize the biology of MET as well as its therapeutic inhibition in lung cancer.
Gene expression profiling following constitutive activation of MEK1 and transformation of rat intestinal epithelial cells
Authors: Koga Komatsu, F Gregory Buchanan, Michiro Otaka, Mario Jin, Masaru Odashima, Yohei Horikawa, Sumio Watanabe, Raymond N DuBois
Journal: Molecular Cancer (2006)

Abstract Background Constitutive activation of MEK1 (caMEK) can induce the oncogenic transformation of normal intestinal epithelial cells. To define the genetic changes that occur during this process, we used oligonucleotide microarrays to determine which genes are regulated following the constitutive activation of MEK in normal intestinal epithelial cells. Results Microarray analysis was performed using Affymetrix GeneChip and total RNA from doxycycline inducible RIEtiCAMEK cells in the presence or absence of doxycycline. MEK-activation induced at least a three-fold difference in 115 gene transcripts (75 transcripts were up-regulated, and 40 transcripts were down-regulated). To verify whether these mRNAs are indeed regulated by the constitutive activation of MEK, RT-PCR analysis was performed using the samples from caMEK expressing RIE cells (RIEcCAMEK cells) as well as RIEtiCAMEK cells. The altered expression level of 69 gene transcripts was confirmed. Sixty-one of the differentially expressed genes have previously been implicated in cellular transformation or tumorogenesis. For the remaining 8 genes (or their human homolog), RT-PCR analysis was performed on RNA from human colon cancer cell lines and matched normal and tumor colon cancer tissues from human patients, revealing three novel targets (rat brain serine protease2, AMP deaminase 3, and cartilage link protein 1). Conclusion Following MEK-activation, many tumor-associated genes were found to have significantly altered expression levels. However, we identified three genes that were differentially expressed in caMEK cells and human colorectal cancers, which have not been previously linked to cellular transformation or tumorogenesis.
Combined Antiretroviral Therapy During Pregnancy and Risk of Congenital Malformations
Authors: Ilona J. Frieden, Anita N. Haggstrom, Charles McCulloch, Beth Drolet, Nancy B. Esterly, Maria C. Garzon, Anne W. Lucky, Eulalia Baselga, Sheila F. Friedlander
Journal: JAMA (2004)
Dual induction of caspase 3- and transglutaminase-dependent apoptosis by acyclic retinoid in hepatocellular carcinoma cells
Authors: Hideki Tatsukawa, Tetsuro Sano, Yayoi Fukaya, Naoto Ishibashi, Makiko Watanabe, Masataka Okuno, Hisataka Moriwaki, Soichi Kojima
Journal: Molecular Cancer (2011)

Abstract Background Hepatocellular carcinoma has a high mortality rate due to its rate of recurrence. Acyclic retinoid prevents recurrence of hepatocellular carcinoma in patients after surgical removal of their primary tumors by inducing apoptosis in hepatocellular carcinoma cells, although the molecular mechanisms of action are not understood. Methods Human hepatocellular carcinoma cells in culture, as well as nude mice transplanted with hepatocellular carcinoma cells and rats given with N -diethylnitrosamine were treated with acyclic retinoid. Changes in activated caspase 3 and transglutaminase 2 (TG2) levels, Sp1 cross-linking and its activities, expression of epidermal growth factor receptor, and apoptotic levels were measured. Results Acyclic retinoid simultaneously stimulated the activation of caspase 3, and the expression, nuclear localization and crosslinking activity of TG2, resulting in crosslinking and inactivation of the transcription factor, Sp1, thereby reducing expression of epidermal growth factor receptor and cell death in three hepatocellular carcinoma cell lines. These effects were partially restored by a caspase inhibitor, transfection of antisense TG2, restoration of functional Sp1, or an excess of epidermal growth factor. Nuclear expression of TG2 and crosslinked Sp1, as also activated caspase 3 were found in both hepatocellular carcinoma cells transplanted into nude mice and cancerous regions within the liver in N -diethylnitrosamine-induced hepatocarcinogenesis model in rats, following treatment of animals with acyclic retinoid. Conclusions Treatment with acyclic retinoid produces a dual activation of caspase 3 and TG2 induced apoptosis of hepatocellular carcinoma cells via modification and inactivation of Sp1, resulting in reduced expression of epidermal growth factor receptor.
Quantification of dyspnoea using descriptors: development and initial testing of the Dyspnoea-12
Authors: J Yorke, S H Moosavi, C Shuldham, P W Jones
Journal: Thorax (2009)

<h3>Rationale:</h3> Dyspnoea is a debilitating and distressing symptom that is reflected in different verbal descriptors. Evidence suggests that dyspnoea, like pain perception, consists of sensory quality and affective components. The objective of this study was to develop an instrument that measures overall dyspnoea severity using descriptors that reflect its different aspects. <h3>Methods:</h3> 81 dyspnoea descriptors were administered to 123 patients with chronic obstructive pulmonary disease (COPD), 129 with interstitial lung disease and 106 with chronic heart failure. These were reduced to 34 items using hierarchical methods. Rasch analysis informed decisions regarding further item removal and fit to the unidimensional model. Principal component analysis (PCA) explored the underlying structure of the final item set. Validity and reliability of the new instrument were further assessed in a separate group of 53 patients with COPD. <h3>Results:</h3> After removal of items with hierarchical methods (n = 47) and items that failed to fit the Rasch model (n = 22), 12 were retained. The "Dyspnoea-12" had good internal reliability (Cronbach's alpha = 0.9) and fit to the Rasch model (χ<sup>2</sup> p = 0.08). Items patterned into two groups called "physical"(n = 7) and "affective"(n = 5). In the separate validation study, Dyspnoea-12 correlated with the Hospital Anxiety and Depression Scale (anxiety <i>r</i> = 0.51; depression <i>r</i> = 0.44, p&lt;0.001, respectively), 6-minute walk distance (r = −0.38, p&lt;0.01) and MRC (Medical Research Council) grade (r = 0.48, p&lt;0.01), and had good stability over time (intraclass correlation coefficient = 0.9, p&lt;0.001). <h3>Conclusion:</h3> Dyspnoea-12 fulfills modern psychometric requirements for measurement. It provides a global score of breathlessness severity that incorporates both "physical" and "affective" aspects, and can measure dyspnoea in a variety of diseases.
Parkinsonism Associated with Alpha-methyldopa Therapy
Authors: M. J. T. Peaston
Journal: BMJ (1964)

A post-mortem examination, carried out by Dr. Boczarow, pathologist at Staincliffe General Hospital, Dewsbury, showed congested brain and meninges.The brain was swollen and there were petechial spots present on the meninges.Cerebral vessels were also dilated.Heart, lungs and pleurae, and other viscera were normal.A specimen of hippocampus and of brain stem was sent to the Public Health Laboratory in London.Its report was as follows:Egg cultutre of a pool of hippocampus and brain stem suspensions No pocks produced on the chorioallantoic membranes of fertile eggs, therefore negative for vaccinia and herpes simplex viruses. BrainHippocampus No Negri bodies seen in stained impression smears.Mouse inoculation Intracerebral.Hippocampus Mice sick with tremors and limb weakness leading to paralysis. 8days post-inoculation impression smears of cut surface of brain-Negri bodies observed. ConclusionRabies virus was present in the specimen of brain.
Ovarian tissue cryopreservation and transplantation: preliminary findings and implications for cancer patients
Authors: K. Oktay
Journal: Human Reproduction Update (2001)

Cancer treatment modalities are increasingly more effective in achieving complete remission and cure. Aggressive chemotherapy and radiotherapy, as well as bone marrow transplantation, results in >90% cure in many cancers of children and young women. As a result of this success however, a new problem has arisen. Many young women survive to live the rest of their lives in menopause, and have no chance of conceiving on their own. Oocyte cryopreservation has resulted in a handful of pregnancies, but the technique may not be applicable to young women and children. Ovarian tissue cryopreservation and transplantation has emerged against this background, first in successful rodent studies, and then in sheep and human ovarian xenograft studies. Because of the encouraging results with animals and xenografts, a human ovarian transplantation trial was launched. Pelvic auto-transplantation of frozen-banked ovarian tissue resulted in ovulation in one patient. Several other patients received fresh grafts subcutaneously, and preliminary results indicated antral follicle development at least in one patient. With the addition of promising data from humans, ovarian tissue cryopreservation from selected patients before cancer treatment, and in those requiring oophorectomy for benign causes, is now advocated.