tbuckley/cabot-search huggingface dataset:
Mutationally Activated PIK3CAH1047R Cooperates with BRAFV600E to Promote Lung Cancer Progression
Authors: Christy L. Trejo, Shon Green, Victoria Marsh, Eric A. Collisson, Gioia Iezza, Wayne A. Phillips, Martin McMahon
Journal: Cancer Research (2013)

Abstract Adenocarcinoma of the lung, a leading cause of cancer death, frequently displays mutational activation of the KRAS proto-oncogene but, unlike lung cancers expressing mutated EGFR, ROS1, or ALK, there is no pathway-targeted therapy for patients with KRAS-mutated lung cancer. In preclinical models, expression of oncogenic KRASG12D in the lung epithelium of adult mice initiates development of lung adenocarcinoma through activation of downstream signaling pathways. In contrast, mutationally activated BRAFV600E, a KRAS effector, fails to initiate lung carcinogenesis despite highly efficient induction of benign lung tumorigenesis. To test if phosphoinositide 3-kinase (PI3K)-α (PIK3CA), another KRAS effector, might cooperate with oncogenic BRAFV600E to promote lung cancer progression, we used mice carrying a conditional allele of Pik3ca that allows conversion of the wild-type catalytic subunit of PIK3CA to mutationally activated PIK3CAH1047R. Although expression of PIK3CAH1047R in the lung epithelium, either alone or in combination with PTEN silencing, was without phenotype, concomitant expression of BRAFV600E and PIK3CAH1047R led to dramatically decreased tumor latency and increased tumor burden compared with BRAFV600E alone. Most notably, coexpression of BRAFV600E and PIK3CAH1047R elicited lung adenocarcinomas in a manner reminiscent of the effects of KRASG12D. These data emphasize a role for PI3K signaling, not in lung tumor initiation per se, but in both the rate of tumor growth and the propensity of benign lung tumors to progress to a malignant phenotype. Finally, biologic and biochemical analysis of BRAFV600E/PIK3CAH1047R-expressing mouse lung cancer cells revealed mechanistic clues about cooperative regulation of the cell-division cycle and apoptosis by these oncogenes. Cancer Res; 73(21); 6448–61. ©2013 AACR.
THE IMMUNOGLOBULINS OF MICE
Authors: John L. Fahey, Stewart Sell
Journal: The Journal of Experimental Medicine (1965)

The metabolic properties of immunoglobulin were investigated by comparing five classes of mouse immunoglobulin. Three forms of 7S immunoglobulin had different rates of catabolism. The fractional rates of catabolism were found to be about 13 per cent per day for 7S gamma(2a)-globulin; 25 per cent for 7S gamma(2b)-globulin; and 17 per cent for 7S gamma(1)-globulin. Catabolism of the three classes of 7S gamma-globulin (gamma(2a), gamma(2b), and gamma(1)) were prolonged at low serum 7S gamma-globulin levels and accelerated at high serum 7S gamma-globulin levels. Each of the 7S gamma-globulin components was influenced by the serum level of the other mouse 7S gamma-globulin components and by exogenously administered human 7S gamma-globulin. They were not appreciably altered, however, by the serum level of IgA (gamma(1)A-, beta(2)A-globulin). The progressively changing (longer) half-times observed in turnover studies of normal IgG (7S gamma-globulin) may be caused by catabolic heterogeneity of normal 7S immunoglobulins which are immunochemically and catabolically related to gamma(2a)-, gamma(2b)-, and 7S gamma(1)-myeloma proteins. These studies indicate that the 7S gamma(2a)-, 7S gamma(2b)-, and 7S gamma(1)-globulins share a common catabolic control mechanism. This mechanism is influenced by the serum level of each of these components, but is independent of the serum level of IgA (gamma(1)A-globulin) and probably is independent of IgM (gamma(1)M-globulin). Catabolism of IgA (gamma(1)A-, beta(2)A-globulin) and IgM (gamma(1)M-globulin) was much more rapid than the catabolism of the 7S gamma-globulins. The halftimes of the IgA and IgM were approximately 1.2 and 0.5 days respectively. The fractional rate of catabolism of IgA and IgM seemed to be independent of their serum concentration. The rate of catabolism, as well as the rate of synthesis, was shown to play a major role in determining the serum level of each class of immunoglobulin.
Methylenetetrahydrofolate Reductase Polymorphisms and Therapy Response in Pediatric Acute Lymphoblastic Leukemia
Authors: Richard Aplenc, Jennifer Thompson, Peggy Han, Mei La, Huaqing Zhao, Beverly Lange, Timothy Rebbeck
Journal: Cancer Research (2005)

Abstract A significant portion of patients treated for pediatric acute lymphoblastic leukemia (ALL) relapse. We hypothesized that common polymorphisms with moderate effect sizes and large attributive risks could explain an important fraction of ALL relapses. Methylenetetrahydrofolate reductase (MTHFR) is central to folate metabolism and has two common functional polymorphisms (C677T and A1298G). Methotrexate (MTX), which interrupts folate metabolism, is a mainstay of pediatric ALL therapy. MTX inhibits the synthesis of dTMP needed for DNA replication by blocking the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate by MTHFR. We hypothesized that a deactivating MTHFR allele would increase ALL relapse risk by potentially increasing 5,10-methylenetetrahydrofolate and dTMP, enhancing DNA synthesis and thus opposing MTX. To test this hypothesis, we genotyped 520 patients on the Children's Cancer Study Group ALL study, CCG-1891. The MTHFR C677T variant allele was statistically significantly associated with relapse (χ2 = 4.38, P = 0.036). This association remained significant (hazard ratio = 1.82, P = 0.008), controlling for important covariates, and was more predictive of relapse than other predictors, including day 7 bone marrow response. The MTHFR C677T variant allele was not associated with an increased risk of toxicity or infection. The MTHFR A1298G polymorphism was not associated with altered risks of relapse, toxicity, or infection. Haplotype analysis showed six common haplotypes that did not provide additional information predictive for relapse. These data provide evidence that the MTHFR C677T polymorphism is a common genetic variant conferring a moderate relative risk and a high attributable risk for relapse in pediatric ALL patients.
COMPARISON OF A NEW ANTIHISTAMINE HC 20–511* WITH CYPROHEPTADINE (PERIACTIN®) IN CHRONIC URTICARIA
Authors: KIRSTI KUOKKANEN
Journal: Allergy (1977)

The effect and tolerance of a new antihistamine, HC 20-511, in daily doses of 2 and 4 mg was compared with cyproheptadine (Periactin) 8 mg daily in 50 cases of chronic urticaria. HC 20-511 4 mg daily proved to be the most effective, rapid and long-lasting. HC 20-511 had less sedative effect than cyproheptadine, but both possessed the same appetite-stimulating effect. However, this was not noted with the smaller dosage of HC 20-511.
Nicotinic Receptors at the Amino Acid Level
Authors: Pierre-Jean Corringer, Nicolas Le Novère, Jean-Pierre Changeux
Journal: The Annual Review of Pharmacology and Toxicology (2000)

nAChRs are pentameric transmembrane proteins into the superfamily of ligand-gated ion channels that includes the 5HT 3 , glycine, GABA A , and GABA C receptors. Electron microscopy, affinity labeling, and mutagenesis experiments, together with secondary structure predictions and measurements, suggest an all-β folding of the N-terminal extracellular domain, with the connecting loops contributing to the ACh binding pocket and to the subunit interfaces that mediate the allosteric transitions between conformational states. The ion channel consists of two distinct elements symmetrically organized along the fivefold axis of the molecule: a barrel of five M2 helices, and on the cytoplasmic side five loops contributing to the selectivity filter. The allosteric transitions of the protein underlying the physiological ACh-evoked activation and desensitization possibly involve rigid body motion of the extracellular domain of each subunit, linked to a global reorganization of the transmembrane domain responsible for channel gating.
Incidence of Death and Acute Myocardial Infarction Associated With Stopping Clopidogrel After Acute Coronary Syndrome
Authors: P. Michael Ho
Journal: JAMA (2008)

It is unknown whether patients are at increased short-term risk for adverse events following clopidogrel cessation.To assess the rates of adverse events after stopping treatment with clopidogrel in a national sample of patients with acute coronary syndrome (ACS).Retrospective cohort study of 3137 patients with ACS discharged from 127 Veterans Affairs hospitals between October 1, 2003, and March 31, 2005, with posthospital treatment with clopidogrel.Rate of all-cause mortality or acute myocardial infarction (AMI) after stopping treatment with clopidogrel.Mean (SD) follow-up after stopping treatment with clopidogrel was 196 (152) days for medically treated patients with ACS without stents (n = 1568) and 203 (148) days for patients with ACS treated with percutaneous coronary intervention (PCI) (n = 1569). Among medically treated patients, mean (SD) duration of clopidogrel treatment was 278 [corrected] (169) [corrected] days and death or AMI occurred in 17.1% (n = 268) of patients, with 60.8% (n = 163) of events occurring during 0 to 90 days, 21.3% (n = 57) during 91 to 180 days, and 9.7% (n = 26) during 181 to 270 days after stopping treatment with clopidogrel. In multivariable analysis including adjustment for duration of clopidogrel treatment, the first 90-day interval after stopping treatment with clopidogrel was associated with a significantly higher risk of adverse events (incidence rate ratio [IRR], 1.98; 95% confidence interval [CI], 1.46-2.69 vs the interval of 91-180 days). Similarly, among PCI-treated patients with ACS, mean (SD) duration of clopidogrel treatment was 302 [corrected] (151) [corrected] days and death or AMI occurred in 7.9% (n = 124) of patients, with 58.9% (n = 73) of events occurring during 0 to 90 days, 23.4% (n = 29) during 91 to 180 days, and 6.5% (n = 8) during 181 to 270 days after stopping clopidogrel treatment. In multivariable analysis including adjustment for duration of clopidogrel treatment, the first 90-day interval after stopping clopidogrel treatment was associated with a significantly higher risk of adverse events (IRR, 1.82; 95% CI, 1.17-2.83).We observed a clustering of adverse events in the initial 90 days after stopping clopidogrel among both medically treated and PCI-treated patients with ACS, supporting the possibility of a clopidogrel rebound effect. Additional studies are needed to confirm the clustering of events after stopping clopidogrel, including associations with cardiovascular mortality and reasons for stopping clopidogrel, as well as to determine the mechanism of this phenomenon, and to identify strategies to reduce early events after clopidogrel cessation.
Incorporation of T and B epitopes of the circumsporozoite protein in a chemically defined synthetic vaccine against malaria.
Authors: J P Tam, P Clavijo, Y A Lu, V Nussenzweig, R Nussenzweig, F Zavala
Journal: The Journal of Experimental Medicine (1990)

We show here an effective and novel approach to engineer peptide-based vaccines using a chemically defined system, known as multiple peptide antigen systems (MAPs), to protect an inbred mouse strain from infection against rodent malaria. 10 mono- and di-epitope MAP models containing different arrangements and stoichiometry of functional B and/or T helper cell epitopes from the circumsporozoite protein of Plasmodium berghei were used to immunize A/J mice. While these mice did not respond to the mono-epitope MAP bearing only the B or T epitope, very high titers of antibody and protective immunity against sporozoite challenge were elicited by di-epitope MAPs, particularly those with the B and T epitopes in tandem and present in equimolar amounts. These results, obtained in a well-defined rodent malaria model, indicate that MAPs may overcome some of the difficulties in the development of synthetic vaccines, not only for malaria but also for other infectious diseases.
Endoscopic snare papillectomy: A single institutional experience of a standardized technique. A retrospective cohort study
Authors: Giovanni D. De Palma, Gaetano Luglio, Francesco Maione, Dario Esposito, Saverio Siciliano, Nicola Gennarelli, Gianluca Cassese, Marcello Persico, Pietro Forestieri
Journal: International Journal of Surgery (2014)
Knee function and knee muscle strength in middle-aged patients with degenerative meniscal tears eligible for arthroscopic partial meniscectomy
Authors: Silje Stensrud, May Arna Risberg, Ewa M Roos
Journal: British Journal of Sports Medicine (2012)

Background Functional limitations exist postmeniscectomy, but preoperative data are scarce. Purpose To examine knee function, knee muscle strength and performance in middle-aged patients with degenerative meniscal tears, eligible for arthroscopic partial meniscectomy. Study design Cross-sectional study. Methods Eighty-two participants with MRI verified degenerative meniscal tear (35% women, mean age 49 years) answered the Knee injury and Osteoarthritis Outcome Score (KOOS) and were tested for isokinetic knee muscle strength and lower extremity performance (one-leg hop for distance, 6 m timed hop and maximum number of knee-bends in 30 s). Limb Symmetry Index (LSI) was used to express side-to-side differences in per cent using the non-injured leg as the control. An LSI ≥90% was considered normal. Results Mean scores of the five subscales of the KOOS were from 13 to 36 points lower compared with a population-based reference group and similar to patients prior to anterior cruciate ligament reconstruction. Quadriceps strength and lower-extremity performance were impaired for the injured leg compared with the non-injured leg (p&lt;0.001), with a mean difference of 13% in quadriceps strength and between 8% and 13% in lower-extremity performance. Between 41% and 52% of the participants had abnormal LSI values in quadriceps muscle strength and lower-extremity performance. Conclusion Middle-aged patients with a symptomatic degenerative meniscal tear experience functional knee problems when eligible for meniscectomy. Included participants reported difficulty with knee pain, symptoms, function and quality of life and quadriceps strength and lower-extremity performance were impaired. Approximately 50% of the study group had clinically relevant impairments in quadriceps strength and lower-extremity performance, defined as &gt;10% differences between the injured and the non-injured leg.
p53 Regulates Metanephric Development
Authors: Zubaida Saifudeen, Susana Dipp, Jana Stefkova, Xiao Yao, Sarah Lookabaugh, Samir S. El-Dahr
Journal: Journal of the American Society of Nephrology (2009)

p53 is best known as a tumor suppressor that regulates cell-cycle, differentiation, and apoptosis pathways, but its potential role in embryonic development and organogenesis remains controversial. Here, p53(-/-) embryos bred on C57Bl6 background exhibited a spectrum of congenital abnormalities of the kidney and urinary tract, including ureteric bud (UB) ectopia, double ureters/collecting systems, delayed primary branching of the UB, and hypoplastic metanephroi. We observed ectopic UB outgrowth from the Wolffian duct (WD) in one third of p53(-/-) embryos. The prevalence of duplex was higher in embryos than in neonates, and ex vivo organ culture suggested that ectopic ureters can regress over time, leaving behind a dysplastic pole ("segmental dysgenesis"). Transgenic expression of dominant negative p53 or conditional inactivation of p53 in the UB but not in the metanephric mesenchyme lineage recapitulated the duplex phenotype. Mechanistically, p53 inactivation in the WD associated with enhanced sensitivity to glial cell line-derived neurotrophic factor (GDNF)-induced ectopic budding and potentiated phosphatidylinositol-3 kinase activation by GDNF in UB cells. Unlike several other models of UB ectopia, hypersensitivity of p53(-/-) WD to GDNF is not accompanied by reduced Sprouty-1 or anterior expansion of the GDNF domain. In summary, our data lend support for a restrictive role for p53 activity in UB outgrowth from the WD.
Ageing does not influence the sleep-related decrease in the hypercapnic ventilatory response
Authors: H.A.K. Browne, L. Adams, A.K. Simonds, M.J. Morrell
Journal: European Respiratory Journal (2003)

In young people, a sleep-related reduction in the gain of the ventilatory chemoreflex feedback loop occurs; in the elderly, it has been reported that no sleep-related reduction occurs. A relatively high loop gain could contribute to periodic breathing and central sleep apnoea in the elderly. This study tested the hypothesis that ageing is associated with a reduction in the magnitude of the sleep-related decrease in the hypercapnic ventilatory response (HCVR). The HCVR was measured using a steady state method, awake and asleep, in groups (n=10) of elderly (66–81 yrs) and young (23–35 yrs) nonapnoeics. Upper airway resistance was maintained close to wakefulness levels using continuous positive airway pressure (mean sleep-related increase in resistance: elderly 1.6±1.2 cmH 2 O·L·s −1 , young 1.2±0.8 cmH 2 O·L·s −1 ). The sleep-related decrease in the HCVR was similar in the elderly and young groups (elderly: wake 0.14±0.06 and sleep 0.06±0.02 L·min −1 ·kPa and young, wake 0.19±0.07 and sleep 0.10±0.04 L·min −1 ·kPa). Ageing per se was shown not to change the magnitude of the sleep-related decrease in hypercapnic ventilatory response. The authors speculate that age-related changes in the hypercapnic ventilatory response are unlikely to contribute to the increased prevalence of central sleep apnoea in the elderly.
Retraction: Application of cytology and molecular biology in diagnosing premalignant or malignant oral lesions
Authors: Ravi Mehrotra, Anurag Gupta, Mamta Singh, Rahela Ibrahim
Journal: Molecular Cancer (2012)

Early detection of a premalignant or cancerous oral lesion promises to improve the survival and the morbidity of patients suffering from these conditions. Cytological study of oral cells is a non-aggressive technique that is well accepted by the patient, and is therefore an attractive option for the early diagnosis of oral cancer, including epithelial atypia and squamous cell carcinoma. However its usage has been limited so far due to poor sensitivity and specificity in diagnosing oral malignancies. Lately it has re-emerged due to improved methods and it's application in oral precancer and cancer as a diagnostic and predictive method as well as for monitoring patients. Newer diagnostic techniques such as brush biopsy and molecular studies have been developed. Recent advances in cytological techniques and novel aspects of applications of scraped or exfoliative cytology for detecting these lesions and predicting their progression or recurrence are reviewed here.
Quantitation of influenza virus antigens on infected target cells and their recognition by cross-reactive cytotoxic T cells.
Authors: C J Hackett, B A Askonas, R G Webster, K van Wyke
Journal: The Journal of Experimental Medicine (1980)

Monoclonal antibody to type-A influenza virus matrix (M)-protein was used to quantitate the appearance of M-protein on abortively infected P815 cells. After 16 h of infection with different type-A viruses, only a low amount of M-protein appears on the surface of infected cells (approximately 10(3) site/cell) in contrast to approximately 10(5) hemagglutinin molecules on each cell surface. However, virus replication is required for M-protein appearance. Analysis of solubilized membranes purified from 16-h-infected cells shows approximately 10(4) M-protein molecule/cell in the plasma membrane, a content that is consistent with the observed low surface expression, and that indicates that most of the M-protein is localized internally. We found no evidence that cross-reactive cytotoxic T cells could recognize M-protein; neither monoclonal antibody or hyperimmune anti-M-protein antiserum could inhibit T cell killing, either alone or in combination with monoclonal anti-H-2 antibody. Taken together, the low level of M-protein appearance and lack of T cell blocking by anti-M-protein antibody leaves doubt that M-protein is the antigen recognized by cross-reactive cytotoxic T cells.
Effects of the thromboxane receptor agonist U46619 and endothelin-1 on large and small airways
Authors: C. Martin, V. Ullrich, S. Uhlig
Journal: European Respiratory Journal (2000)

Recently attention has been drawn to the role of small airways in asthma. However, little information exists about the responsiveness of small airways to various bronchoconstrictors in comparison to large airways. In this study, the model of precision-cut lung slices (PCLSs) was used to investigate the effects of the thromboxane receptor agonist U46619 and endothelin (ET)-1 on small (diameter <250 microm), medium (250-420 microm) and large (>420 microm) airways. Viable PCLSs were prepared from rat lungs and the bronchoconstriction of differently sized airways inducible by U46619 and ET-1 was observed by means of a microscope and analysed by digital imaging techniques. The median effective concentration (EC50) of U46619 for inducing bronchoconstriction was 6.9 nM in small and 66 nM in large airways, respectively. This finding was corroborated by direct observations in single lung slices containing both a small and a large airway. In such slices, U46619 caused smaller airways to contract to a greater degree than larger ones. ET-1 induced bronchoconstriction was similar in small (EC50 34 nM) and in medium or large (ECso 22 nM) airways. This was again confirmed by direct observation of ET-1-treated PCLSs. It is concluded that, in rat lungs, endothelin-1 affects small and large airways to the same extent, whereas thromboxane is ten times more potent in causing small airways to contract than larger ones. Precision-cut lung slices appear to be a valuable model for examining the (patho)physiology of small airways.
The role of NIV in post-extubation respiratory failure
Authors: N M Rahman
Journal: Thorax (2004)

▴ Esteban A, Frutos-Vivar F, Ferguson ND, et al . Noninvasive positive-pressure ventilation for respiratory failure after extubation. N Engl J Med2004;350:2452–60. [OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] Whilst non-invasive ventilation (NIV) has an established role in treating acute on chronic respiratory failure, its impact on re-intubation rate following elective extubation and subsequent respiratory failure is unclear. This multicentre, randomised, controlled trial addressed whether use of NIV after discontinuation of mechanical ventilation can decrease mortality (primary outcome) or … [1]: {openurl}?query=rft.jtitle%253DNew%2BEngland%2BJournal%2Bof%2BMedicine%26rft.stitle%253DNEJM%26rft.issn%253D0028-4793%26rft.aulast%253DEsteban%26rft.auinit1%253DA.%26rft.volume%253D350%26rft.issue%253D24%26rft.spage%253D2452%26rft.epage%253D2460%26rft.atitle%253DNoninvasive%2BPositive-Pressure%2BVentilation%2Bfor%2BRespiratory%2BFailure%2Bafter%2BExtubation%26rft_id%253Dinfo%253Adoi%252F10.1056%252FNEJMoa032736%26rft_id%253Dinfo%253Apmid%252F15190137%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1056/NEJMoa032736&link_type=DOI [3]: /lookup/external-ref?access_num=15190137&link_type=MED&atom=%2Fthoraxjnl%2F59%2F9%2F745.atom [4]: /lookup/external-ref?access_num=000221887200004&link_type=ISI