tbuckley/cabot-search huggingface dataset:
Identification of the Ubiquitin-Proteasome Pathway in the Regulation of the Stability of Eukaryotic Elongation Factor-2 Kinase
Authors: Sonia Arora, Jin-Ming Yang, William N. Hait
Journal: Cancer Research (2005)

Abstract Eukaryotic elongation factor-2 kinase (eEF-2 kinase) is a highly conserved calcium/calmodulin-dependent enzyme involved in the regulation of protein translation and cell proliferation. Rapid changes in the activity and abundance of eEF-2 kinase have been observed on growth stimulation, and increased enzyme activity is characteristic of malignant cell growth. Yet the mechanism for controlling the turnover of this kinase is unknown. The ubiquitin-proteasome pathway regulates the degradation of many cellular proteins, including transcription factors, cell cycle regulators, and signal transduction proteins. Therefore, we determined whether the ubiquitin-proteasome pathway regulates the turnover of eEF-2 kinase. We found that eEF-2 kinase was a relatively short-lived protein with a half-life of less than 6 hours. eEF-2 kinase was ubiquitinated in vivo as determined by coimmunoprecipitation and polyubiquitin affinity matrix. Incubation of purified eEF-2 kinase with a source of ubiquitination enzymes (rabbit reticulocyte lysate), purified ubiquitin, and ATP revealed the presence of increasing molecular weight species of ubiquitinated eEF-2 kinase. Treatment of cells with MG132, a proteasome inhibitor, inhibited eEF-2 kinase degradation and induced the accumulation of polyubiquitinated forms of the enzyme, resulting in an increase in its half-life. These results suggest involvement of the proteasome in the turnover of the ubiquitinated kinase. Because eEF-2 kinase is chaperoned by heat shock protein 90 (Hsp90), we next determined if disruption of the Hsp90-eEF-2 kinase complex promoted degradation of the kinase. Treatment of cells with geldanamycin, an Hsp90 inhibitor, enhanced ubiquitination of eEF-2 kinase and decreased the half-life of the kinase to less than 2 hours. These results indicate that cellular levels of eEF-2 kinase are maintained by a balance between association with Hsp90 and degradation by the ubiquitin-proteasome pathway. In conclusion, these data show that the turnover of eEF-2 kinase is regulated by the ubiquitin-proteasome pathway and, therefore, modulating the ubiquitination of eEF-2 kinase might control the abundance of this enzyme and have implications in the treatment of certain forms of cancer.
Asymmetric Context-Dependent Mutation Patterns Revealed through Mutation–Accumulation Experiments
Authors: Way Sung, Matthew S. Ackerman, Jean-François Gout, Samuel F. Miller, Emily Williams, Patricia L. Foster, Michael Lynch
Journal: Molecular Biology and Evolution (2015)

Despite the general assumption that site-specific mutation rates are independent of the local sequence context, a growing body of evidence suggests otherwise. To further examine context-dependent patterns of mutation, we amassed 5,645 spontaneous mutations in wild- type (WT) and mismatch-repair deficient (MMR–) mutation–accumulation (MA) lines of the gram-positive model organism Bacillus subtilis. We then analyzed>7,500 spontaneous base-substitution mutations across B. subtilis, Escherichia coli, and Mesoplasma florum WT and MMR– MA lines, finding a context-dependent mutation pattern that is asymmetric around the origin of replication. Different neighboring nucleotides can alter site-specific mutation rates by as much as 75-fold, with sites neighboring G:C base pairs or dimers involving alternating pyrimidine–purine and purine–pyrimidine nucleotides having significantly elevated mutation rates. The influence of context-dependent mutation on genome architecture is strongest in M. florum, consistent with the reduced efficiency of selection in organisms with low effective population size. If not properly accounted for, the disparities arising from patterns of context-dependent mutation can significantly influence interpretations of positive and purifying selection.
THE SOURCE OF THE MICROORGANISMS IN THE LUNGS OF NORMAL ANIMALS
Authors: F. S. Jones
Journal: The Journal of Experimental Medicine (1922)

It has been possible to show that the lungs of such animals as the calf, rabbit, guinea pig, white rat, and white mouse are readily invaded by organisms. The most frequent types observed in cultures from the border of the lungs have been streptothrix, molds, and bacteria of the Bacillus subtilis group. These forms originate in certain dry food stuffs (hay and straw). By withholding or moistening these materials it has been possible to diminish the number of organisms in the lungs. When these materials have been supplied to mice whose lungs under usual conditions contain only a few organisms, the number of positive cultures increases and is comparable with those of the larger animals. The bronchial lymph glands of all guinea pigs examined developed, in 66(2/3) per cent of the tubes, organisms similar to those obtained from the lungs.
Pulmonary sensitivity to nitrofurantoin.
Authors: J Hart
Journal: BMJ (1970)

BDIC 51Tolerance of Rifampicin SIR,-One of the virtues of rifampicin is said to be a good patient tolerance which, as you have noted (30 August, 1969, p. 487), should be particularly valuable in treatment of tuberculosis where tolerance is poor.To demonstrate objectively whether this good tolerance extends to domiciliary ambulant therapy we have used a simple urine test for rifampicin on patients attending the Dagenham Chest Clinic, consecutively during June, July, August, and September last year (Table ).During the same period we examined urines of all patients on P.A.S., using Phenistix.1 |No. of patientsIPositive Negative Rifampicin (Butanol)
Slipping the barrier: how variants in CARD15 could alter permeability of the intestinal wall and population health
Authors: S Schreiber
Journal: Gut (2006)

The increased intestinal permeability in Crohn's disease is associated with the presence of variants in the CARD15 gene that are regarded as causative for Crohn's disease, suggesting a genetic rather than an environmental background for intestinal barrier dysfunction in Crohn's disease
Immunopathogenesis of Rheumatoid Arthritis
Authors: D. L. Gardner
Journal: Annals of the Rheumatic Diseases (1980)

chapter on rehabilitation aspects, but the sophisticated and annotated approach in both of them tends to obscure the simplicity of such measures as static quadriceps drill and wrist extension exercises, which to an informed patient will make-at the cost of 5 minutes of the physician's time-all the difference between a useful limb and functional incapacity.But these and one or two other points of detail are only minor criticisms of an exhaustive textbook.Exhaustive it must have been.Joe Hollander and I compared notes (I had recently edited the most recent edition of the book's British counterpart) while we cruised up the Rhine together during the Wiesbaden conference of September 1979.'You know, Tom', he reflected, 'I reckon that producing an edition of a book like this takes 2 years out of your life'.I agreed in principle, though admittedly never having considered the matter in actuarial terms.British rheumatologists will also agree with me in congratulating Dr McCarty and his many colleagues on the fruits of their labours, yet another edition of almost impeccable excellence.
Evaluation of p21 promoter for interleukin 12 radiation induced transcriptional targeting in a mouse tumor model
Authors: Urska Kamensek, Gregor Sersa, Maja Cemazar
Journal: Molecular Cancer (2013)

Abstract Background Radiation induced transcriptional targeting is a gene therapy approach that takes advantage of the targeting abilities of radiotherapy by using radio inducible promoters to spatially and temporally limit the transgene expression. Cyclin dependent kinase inhibitor 1 (CDKN1A), also known as p21, is a crucial regulator of the cell cycle, mediating G1 phase arrest in response to a variety of stress stimuli, including DNA damaging agents like irradiation. The aim of the study was to evaluate the suitability of the p21 promoter for radiation induced transcriptional targeting with the objective to test the therapeutic effectiveness of the combined radio-gene therapy with p21 promoter driven therapeutic gene interleukin 12. Methods To test the inducibility of the p21 promoter, three reporter gene experimental models with green fluorescent protein (GFP) under the control of p21 promoter were established by gene electrotransfer of plasmid DNA: stably transfected cells, stably transfected tumors, and transiently transfected muscles. Induction of reporter gene expression after irradiation was determined using a fluorescence microplate reader in vitro and by non-invasive fluorescence imaging using fluorescence stereomicroscope in vivo . The antitumor effect of the plasmid encoding the p21 promoter driven interleukin 12 after radio-gene therapy was determined by tumor growth delay assay and by quantification of intratumoral and serum levels of interleukin 12 protein and intratumoral concentrations of interleukin 12 mRNA. Results Using the reporter gene experimental models, p21 promoter was proven to be inducible with radiation, the induction was not dose dependent, and it could be re-induced. Furthermore radio-gene therapy with interleukin 12 under control of the p21 promoter had a good antitumor therapeutic effect with the statistically relevant tumor growth delay, which was comparable to that of the same therapy using a constitutive promoter. Conclusions In this study p21 promoter was proven to be a suitable candidate for radiation induced transcriptional targeting. As a proof of principle the therapeutic value was demonstrated with the radio-inducible interleukin 12 plasmid providing a synergistic antitumor effect to radiotherapy alone, which makes this approach feasible for the combined treatment with radiotherapy.
A steganalysis-based approach to comprehensive identification and characterization of functional regulatory elements.
Authors: Guandong Wang, Weixiong Zhang
Journal: Genome biology (2006)

Abstract The comprehensive identification of cis -regulatory elements on a genome scale is a challenging problem. We develop a novel, steganalysis-based approach for genome-wide motif finding, called WordSpy, by viewing regulatory regions as a stegoscript with cis -elements embedded in 'background' sequences. We apply WordSpy to the promoters of cell-cycle-related genes of Saccharomyces cerevisiae and Arabidopsis thaliana , identifying all known cell-cycle motifs with high ranking. WordSpy can discover a complete set of cis -elements and facilitate the systematic study of regulatory networks.
The Outcome of Liver Transplantation in Patients With Hepatocellular Carcinoma in the United States Between 1988 and 2001: 5-Year Survival Has Improved Significantly With Time
Authors: Hwan Y. Yoo, Cary H. Patt, Jean-Francois Geschwind, Paul J. Thuluvath
Journal: Journal of Clinical Oncology (2003)

We hypothesized that the outcome of liver transplantation in patients with hepatocellular carcinoma (HCC) has improved over the past decade because of the application of published criteria for patient selection. In this study, we compared the outcome of liver transplantation in patients with and without HCC at different time periods using the United Network for Organ Sharing data.We excluded children, patients with multiple organ transplantation or retransplantation, and those with incomplete survival data. The study period was arbitrarily divided into three time intervals: 1987 to 1991, 1992 to 1996, and 1997 to 2001.During the study period, 985 patients with HCC (HCC group), and 33,339 without HCC underwent liver transplantation (control group). Kaplan-Meier patient and graft survivals were significantly lower for the HCC group compared with the control group. Cox regression analysis (after adjusting for other confounding variables) confirmed a lower patient survival in the HCC group (1-year survival, 77.0% v 86.7%; hazard ratio [HR], 1.7; 95% CI, 1.5 to 2.0; P <.0001) compared with the control group (5-year survival, 48.2% v 74.7%; HR, 2.2; 95% CI, 1.9 to 2.4; P <.0001); HCC was an independent predictor of survival. Kaplan-Meier analysis showed a significant improvement in 5-year patient survival with time in patients with HCC (1987 to 1991, 25.3%; 1992 to 1996, 46.6%; 1997 to 2001, 61.1%; P <.0001). During the same period, there was only minimal improvement in survival among the control group.Five-year survival of patients transplanted for HCC is excellent, with a steady improvement in survival over the past decade. It is possible that the published criteria for patient selection may have contributed to the better outcome.
Lung epithelial pten controls epithelial barrier integrity in vitro and in vivo
Authors: Shigehisa Yanagi, Hironobu Tsubouchi, Nobuhiro Matsumoto, Masamitsu Nakazato
Journal: European Respiratory Journal (2013)

Exploration of the mechanisms of alveolar epithelial cells (AECs) integrity is important for understanding the pathogenesis of acute lung injury. The tight junctions (TJs) of AECs provide intercellular sealing and are integral to the maintenance of the integrity of the alveolar-capillary barrier. However, the mechanisms regulating AEC barrier integrity are not fully understood. We explored the role of epithelial Pten in lung injury by using lung-epithelium specific Pten-deficient (SOPten) mice. We also investigated the function of Pten by using stably introduced lentivirus encoding either wild-type PTEN (lenti-PTEN-WT) or dominant-negative mutant of PTEN (lenti-PTEN-CS) in BEAS-2B. SOPten lungs after bleomycin or lipopolysaccharide injury exhibited extensive intralveolar edema and increased alveolar permeability. SOPten lungs demonstrated loss of TJs morphology and dissociation of cell-cell contacts after injury. Levels of TJs protein were decreased in SOPten lungs after injury. Exogenous expressions of PTEN were observed in the lenti-PTEN-WT and lenti-PTEN-CS transfected cells. Expression of WT PTEN abolished Akt phosphorylation, whereas that of PTEN-CS increased pAkt levels in BEAS-2B cells. After treatment with transforming growth factor (TGF)-beta1, monolayers of the lenti-PTEN-WT cells showed retained transpeithelial electrical resistance (TER) levels compared with those of untreated cells. In contrast, monolayers of the lenti-PTEN-CS cells exhibited a substantial reduction of TER after TGF-beta1 treatment. Levels of TJs protein were severely attenuated in the TGF-beta1-treated lenti-PTEN-CS cells. These findings reveal that epithelial Pten is crucial guardian controlling AECs barrier integrity.
Chronic intestinal pseudo-obstruction in systemic lupus erythematosus
Authors: G Perlemuter, S Chaussade, B Wechsler, P Cacoub, M Dapoigny, A Kahan, P Godeau, D Couturier
Journal: Gut (1998)

Background/Aims —Chronic intestinal pseudo-obstruction (CIPO) reflects a dysfunction of the visceral smooth muscle or the enteric nervous system. Gastrointestinal manifestations are common in systemic lupus erythematosus (SLE) but CIPO has not been reported. Features of CIPO are reported in five patients with SLE. Methods —From 1988 to 1993, five patients with SLE or SLE-like syndrome were hospitalised for gastrointestinal manometric studies. CIPO was the onset feature in two cases. Antroduodenal manometry (three hours fasting, two hours fed) was performed in all patients, and oesophageal manometry in four. Results —Intestinal hypomotility associated with reduced bladder capacity and bilateral ureteral distension was found in four patients and aperistalsis of the oesophagus in three. Treatment, which consisted of high dose corticosteroids, parenteral nutrition, promotility agents, and antibiotics, led to remission of both CIPO and urinary abnormalities in all cases. Antroduodenal manometry performed in two patients after remission showed increased intestinal motility. One patient died, and postmortem examination showed intestinal vasculitis. Conclusions —CIPO in SLE is a life threatening situation that can be reversed by treatment. It may be: ( a ) a complication or onset feature of the disease; ( b ) secondary to smooth muscle involvement; ( c ) associated with ureteral and vesical involvement; ( d ) the result of intestinal vasculitis.
Influence of age on operative mortality and long‐term survival after lung resection for bronchogenic carcinoma
Authors: M. de Perrot, M. Licker, M.A. Reymond, J. Robert, A. Spiliopoulos
Journal: European Respiratory Journal (1999)

The proportion of elderly patients presenting with bronchogenic carcinoma is increasing. To study the impact of age on clinical presentation, management and outcome of patients, the authors have reviewed their clinical experience over the last 20 yrs. Between 1977 and 1996, 1,079 patients underwent thoracotomy for primary lung carcinoma in the authors' institution. Patients were grouped by age at the time of surgery as <60 yrs, 60-69 yrs and > or =70 yrs. Although the mode of clinical presentation was similar between all age groups, patients <60 yrs were more prone to have advanced stage carcinoma at the time of diagnosis. The rates of exploratory thoracotomy and pneumonectomy were higher in patients <70 yrs, whereas lobectomies and lesser resections largely predominated in patients > or =70 yrs. The mortality rate following lobectomy and lesser resection increased from 1.3% in patients <60 yrs to 5.5% in patients > or =60 yrs (p=0.04) and the mortality rate following pneumonectomy increased from 6.5% in patients <60 yrs to 13.7% in patients > or =70 yrs (p=0.24). The specific long-term survival, which included only the patients who died from primary lung carcinoma, was similar in all age groups. Operative mortality and survival rates are acceptable in patients > or =70 yrs. Therefore, age in itself should not constitute a contraindication to surgical lung resection for primary lung carcinoma as long as a careful preoperative assessment is performed to appropriately select surgical candidates.
P16 reactivation induces anoikis and exhibits antitumour potency by downregulating Akt/survivin signalling in hepatocellular carcinoma cells
Authors: H. Hu, Z. Li, J. Chen, D. Wang, J. Ma, W. Wang, J. Li, H. Wu, L. Li, M. Wu, Q. Qian, J. Chen, C. Su
Journal: Gut (2010)

Hepatocellular carcinoma (HCC) is one of the most malignant tumours with high rate of recurrence and metastasis. In HCC, deficiency of the P16/CDK4/Rb pathway is a frequent molecular event, and transferring the P16 gene into cancer cells can induce cell cycle arrest and apoptosis, suggesting that the P16 gene is a good target in cancer gene therapy. The previous study demonstrated that P16 re-expression mediated by adenovirus within cancer cells can induce cell apoptosis and exert potent antitumour efficacy in cancer xenografts in nude mice. However, the molecular mechanism of P16-induced apoptosis in cancer cells is not clear yet. In this resulting study, we found that P16 re-expression can downregulate survivin expression in HCC cells. As a member of the inhibitors of the apoptotic gene family, survivin has been reported to be overexpressed in most common human cancers and present multiple physiological and pathological functions including cell cycle control, inhibition of cell apoptosis, regulation of cell division and induction of angiogenesis, etc. Further investigation found that P16 reactivation led to a decrease of phosphorylated Akt on Thr308 and phosphorylated survivin on Thr34, then downregulated survivin expression. The P16-mediated decrease of nuclear survivin in cancer cells limited CDK4 import into nuclei, which restrained CDK4 functions of promoting cell proliferation, then exhibited the effect of cell cycle arrest and induction of detachment-induced apoptosis (anoikis). The antitumor potency of P16 by downregulating the Akt/survivin signalling was also demonstrated in HCC xenograft models in nude mice. This new insight into P16 function would help in designing better strategies for cancer gene therapy.
The activated mesangial cell
Authors: R J Johnson, J Floege, A Yoshimura, H Iida, W G Couser, C E Alpers
Journal: Journal of the American Society of Nephrology (1992)

The glomerular mesangial cell may have several important beneficial functions in the normal glomerulus. These include the production of growth factors to allow normal cell turnover, the provision of structural support for the capillaries via the production of mesangial matrix, and the modulation of glomerular hemodynamics via their contractile properties. However, in various types of glomerular injury, the mesangial cell may acquire characteristics of a "myofibroblast", which may in fact be injurious to the glomerulus. These "activated" mesangial cells can be shown to be proliferating by one or more mechanisms that are mediated by platelets and that also involve the local production of platelet-derived growth factor. Like myofibroblasts in other tissues, the mesangial cell acquires smooth muscle cell-like properties, characterized by the de novo expression of alpha-smooth muscle actin, and by the development of fibroblast-like properties, characterized by the production of interstitial collagens in addition to normal mesangial matrix constituents. Identifying therapeutic strategies that prevent this phenotypic modulation of the mesangial cell may provide new ways to treat golmerular diseases.
Determinants of Prostate Cancer–Specific Survival After Radiation Therapy for Patients With Clinically Localized Prostate Cancer
Authors: Anthony V. D’Amico, Kerri Cote, Marian Loffredo, Andrew A. Renshaw, Delray Schultz
Journal: Journal of Clinical Oncology (2002)

Identifying pretreatment and posttreatment predictors of time to prostate cancer-specific death (PCSD) after external-beam radiation therapy (RT) was the subject of this study.A Cox regression analysis was used to evaluate the ability of the pretreatment risk group to predict time to PCSD for 381 patients who underwent RT for clinically localized prostate cancer. Posttreatment factors analyzed for the 94 patients who experienced prostate-specific antigen (PSA) failure included the time to PSA failure, the posttreatment PSA doubling time (DT), and the timing of salvage hormonal therapy.Despite the median age of 73 years at diagnosis, 45% of patients with high-risk disease were estimated to die from prostate cancer within 10 years after RT compared with 0% (P =.004) and 6% (P =.05) for patients with low- or intermediate-risk disease, respectively. Predictors of time to PCSD after PSA failure included PSA DT (P =.01) and delayed use of hormonal therapy (P <or=.002). Nearly identical estimates of PCSD and all-cause death after PSA failure were noted for patients with a short PSA DT (ie, <or= 12 months).Prostate cancer was a major cause of death during the first decade after RT for patients with clinically localized but high-risk disease, and the cause of death for patients with a short PSA DT after RT was nearly always prostate cancer. These data provide evidence to propose the hypothesis that a short posttreatment PSA DT may serve as a possible surrogate for PCSD. Prospective validation is needed.