tbuckley/cabot-search huggingface dataset:
Phospho-ERM localization in UIP specimens: An immunohistochemystry approach
Authors: Simona Inghilleri, Giulia Maria Stella, Michele Zorzetto, Ilaria Campo, Patrizia Morbini, Tiberio Oggionni, Maurizio Luisetti
Journal: European Respiratory Journal (2011)

Background: Idiopathic Pulmonary Fibrosis (IPF) is a progressive, fatal lung disease of unknown etiology still lacking of effective therapy. IPF has a poor prognosis with a median survival of 2.5-3.5 years, and it is associated with lung cancer with a prevalence ranging from 4.8% to 48%. Molecular mechanisms of carcinogenesis occurring in IPF remain to be clarified.

Aim and objective: The family of ezrin/radixin/moesin (ERM) proteins is essential for maintenance of cell shape, cell adhesion, migration and division, serving as an important cross-linker between the plasma membrane and cytoskeleton. Recent studies showed that ERM is upregulated in multiple types of metastatic cancers. In the current investigation, we tested the hypothesis that ERM interacts and play a key role in epithelial-mesenchimal transition (EMT) in alveolar epithelial cells.

Methods: In order to identify the relationship between lung cancer and IPF we assessed an immunohistochemistry analysis for phospho-ERM in the following pulmonary biopsy specimens: 20 IPF/UIP, 4 adenocarcinoma, 6 cryptogenic organizing pneumonia (COP), and 4 normal controls.

Results: Our preliminary data showed in normal lung samples a totally negative phospho-ERM immunostaining. We found a weak positivity in COP samples, whereas in UIP samples we found a higher global expression, in particular in activated type II pneumocytes and basal bronchiolar cells.

Conclusion: We hypothesize that activation of ERM proteins could be involved in UIP pathogenesis, leading to possible contribute to the EMT process of lung epithelial cells.
Immunologic Self-Tolerance Maintained by Cd25+Cd4+Regulatory T Cells Constitutively Expressing Cytotoxic T Lymphocyte–Associated Antigen 4
Authors: Takeshi Takahashi, Tomoyuki Tagami, Sayuri Yamazaki, Toshimitsu Uede, Jun Shimizu, Noriko Sakaguchi, Tak W. Mak, Shimon Sakaguchi
Journal: The Journal of Experimental Medicine (2000)

This report shows that cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) plays a key role in T cell–mediated dominant immunologic self-tolerance. In vivo blockade of CTLA-4 for a limited period in normal mice leads to spontaneous development of chronic organ-specific autoimmune diseases, which are immunopathologically similar to human counterparts. In normal naive mice, CTLA-4 is constitutively expressed on CD25+CD4+ T cells, which constitute 5–10% of peripheral CD4+ T cells. When the CD25+CD4+ T cells are stimulated via the T cell receptor in vitro, they potently suppress antigen-specific and polyclonal activation and proliferation of other T cells, including CTLA-4–deficient T cells, and blockade of CTLA-4 abrogates the suppression. CD28-deficient CD25+CD4+ T cells can also suppress normal T cells, indicating that CD28 is dispensable for activation of the regulatory T cells. Thus, the CD25+CD4+ regulatory T cell population engaged in dominant self-tolerance may require CTLA-4 but not CD28 as a costimulatory molecule for its functional activation. Furthermore, interference with this role of CTLA-4 suffices to elicit autoimmune disease in otherwise normal animals, presumably through affecting CD25+CD4+ T cell–mediated control of self-reactive T cells. This unique function of CTLA-4 could be exploited to potentiate T cell–mediated immunoregulation, and thereby to induce immunologic tolerance or to control autoimmunity.
Post-Translational Modification By Serine Proteases Controls The CCL23 Activity In Nasal Polyps Of Chronic Rhinosinusitis
Authors: Atsushi Kato, Anjeni Keswani, Julie Kim, Julie Poposki, Sarah Peterson, Lydia Suh, James Norton, Anju T. Peters, Kathryn E. Hulse, Leslie C. Grammer, Bruce K. Tan, Rakesh Chandra, David Conley, Juan Jaen, Thomas Schall, Robert C. Kern, Robert P. Schleimer
Journal: Journal of Allergy and Clinical Immunology (2014)
Physiologic changes before and after radiation treatment for carcinoma of the lung
Authors: P. A. Germon
Journal: JAMA (1968)

Physiologic data concerning 30 patients with bronchogenic carcinoma were obtained before radiation therapy and at intervals thereafter. At pretreatment examination, abnormalities were found in all patients. Postirradiation data revealed decreased residual volumes and diffusing capacities with little progression of airway obstruction. No parameter evaluated demonstrated correlation with the volume dose of the tissue irradiated. Pretreatment lung scintiscans disclosed areas of decreased capillary blood flow which were greater at times than would be suggested by chest roentgenograms. Postirradiation lung scans showed further decreases in the pulmonary capillary blood flow in areas initially affected. It is suggested that alterations in the capillary blood flow and resultant tissue changes were initiated by tumor and aggravated by radiation therapy. The data do not confirm other reports attributing the development of severe pulmonary disability to radiation therapy of the lung.
Randomized Controlled Trial of Once- Versus Thrice-Daily Tobramycin in Febrile Neutropenic Children Undergoing Stem Cell Transplantation
Authors: L. Sung, L. L. Dupuis, B. Bliss, A. Taddio, M. Abdolell, U. Allen, M. Rolland, A. Tong, T. Taylor, J. Doyle
Journal: JNCI Journal of the National Cancer Institute (2003)

Background: The benefits of aminoglycoside antibiotics, such as tobramycin, administered as a once-daily dose to manage febrile neutropenia, have been demonstrated in many patient populations. However, toxicity and safety data are lacking for pediatric stem cell transplant recipients, who are at especially high risk for aminoglycoside-related toxicity and infectious morbidity. In particular, the relative nephrotoxicity and efficacy of tobramycin administered as a single daily dose or as three daily doses among this patient population is not known. Methods: We conducted a randomized, double-blind controlled study of tobramycin dosing among children 18 years or younger who had fever and neutropenia while undergoing stem cell transplantation. From October 2000 through November 2002, 60 children were randomly assigned to receive intravenous tobramycin, as either a single daily dose (n = 29) or every 8 hours (n = 31), in combination with either piperacillin or ceftazidime (intravenous). Tobramycin doses were adjusted to achieve pharmacokinetic targets. The primary outcome was nephrotoxicity, as represented by the maximal percent increase in serum creatinine concentration throughout the episode of febrile neutropenia relative to the baseline serum creatinine concentration. Efficacy was a secondary outcome and was defined as survival of the episode without modification of the antibacterial regimen. All statistical tests were two-sided. Results: In a modified intent-to-treat analysis, the mean maximal percent increase in serum creatinine concentration was 32% (N = 26) in the once daily dose group and 51% (N = 28) in the every 8 hours dose group (difference = 19%, 95% confidence interval [CI] = 0% to 38%; P = .054). Among patients evaluable for efficacy, 12 (46%) of 26 patients in the once daily dose group and five (19%) of 27 patients in the every 8 hours dose group survived the episode of febrile neutropenia without requiring antibacterial treatment modification (difference = 27%, 95% CI = 4% to 52%; P = .03). There was one death in each group. Conclusions: In febrile neutropenic children undergoing stem cell transplantation, tobramycin may be less nephrotoxic and more efficacious when administered as a once daily dose than when administered every 8 hours.
Association of Depressed Myofibrillar Adenosine Triphosphatase and Reduced Contractility in Experimental Heart Failure
Authors: BRIAN M. CHANDLER, EDMUND H. SONNENBLICK, JAMES F. SPANN, PETER E. POOL
Journal: Circulation Research (1967)

Although previous studies have suggested a depression of myofibrillar ATPase in the presence of heart failure, their interpretation has been limited by failure to exclude mitochondrial contamination and lack of information regarding the contractility of the tissue studied. To explore this fundamental question, myofibrils were prepared from the right and left ventricles of 15 normal cats, 10 cats with right ventricular hypertrophy and 19 with right ventricular hypertrophy and right ventricular failure, the latter groups following graded pulmonary artery stenosis. The contractility of these hearts was assessed using their right ventricular papillary muscles isolated in a myograph. Myofibrillar ATPase in all groups was maximally activated by 5 mM ATP, 5 mM MgCl 2 at pH 7.0 and 37°C, while mitochondrial contamination was eliminated by sodium azide. In right ventricular failure, right ventricular myofibrillar ATPase was depressed by 39% from an average of 0.18±0.01 in normal cats to 0.11±0.01 µmole inorganic phosphate/mg protein per min (P&lt;.001). In right ventricular hypertrophy, right ventricular myofibrillar ATPase was not significantly depressed (0.16±0.01 µmole/mg per min). Of note, left ventricular myofibrillar ATPase was also significantly (P&lt;.05) depressed in right ventricular failure from 0.16±0.01 to 0.13±0.01 µmole/mg per min. Contractility of the associated right ventricular papillary muscles, expressed as maximum rate of force development at the apex of the length-active tension curve, was correlated with myofibrillar ATPase activity.
<i>Klebsiella oxytoca</i>as a Causative Organism of Antibiotic-Associated Hemorrhagic Colitis
Authors: Christoph Högenauer, Cord Langner, Eckhard Beubler, Irmgard T. Lippe, Rudolf Schicho, Gregor Gorkiewicz, Robert Krause, Nikolas Gerstgrasser, Guenter J. Krejs, Thomas A. Hinterleitner
Journal: New England Journal of Medicine (2006)

Antibiotic-associated hemorrhagic colitis is a distinct form of antibiotic-associated colitis in which Clostridium difficile is absent. Although the cause is not known, previous reports have suggested a role of Klebsiella oxytoca.We studied 22 consecutive patients who had suspected antibiotic-associated colitis and who were negative for C. difficile. Patients underwent diagnostic colonoscopy, and among those who received a diagnosis of antibiotic-associated hemorrhagic colitis, stool samples were cultured for K. oxytoca. We isolated K. oxytoca strains and tested them for cytotoxin production using a tissue-culture assay. In addition, we also cultured stool samples obtained from 385 healthy subjects for K. oxytoca. An in vivo animal model for antibiotic-associated hemorrhagic colitis was established with the use of Sprague-Dawley rats.Of the 22 patients, 6 had findings on colonoscopy that were consistent with the diagnosis of antibiotic-associated hemorrhagic colitis, and 5 of these 6 patients had positive cultures for K. oxytoca. No other common enteric pathogens were found in the five patients. Before the onset of colitis, all five were receiving penicillins, and two were also taking nonsteroidal antiinflammatory drugs (NSAIDs). All isolated K. oxytoca strains produced cytotoxin. K. oxytoca was found in 1.6% of the healthy subjects. In the animal model, K. oxytoca was found only in the colon of rats that received amoxicillin-clavulanate in addition to being inoculated with K. oxytoca. In these rats, infection with K. oxytoca induced a right-sided hemorrhagic colitis that was not observed in uninfected animals that received amoxicillin-clavulanate, indomethacin (an NSAID), or both.Our fulfillment of Koch's postulates for cytotoxin-producing K. oxytoca suggests that it is the causative organism in at least some cases of antibiotic-associated hemorrhagic colitis. Infection with K. oxytoca should be considered in patients with antibiotic-associated colitis who are negative for C. difficile.
Glue-sniffing and distal renal tubular acidosis
Authors: E J Carlisle, S M Donnelly, S Vasuvattakul, K S Kamel, S Tobe, M L Halperin
Journal: Journal of the American Society of Nephrology (1991)

An index case is presented to introduce the subject of the acid-base and electrolyte abnormalities resulting from toluene abuse. These include metabolic acidosis associated with a normal anion gap and excessive loss of sodium and potassium in the urine. The major question addressed is, what is the basis for the metabolic acidosis? Overproduction of hippuric acid resulting from the metabolism of toluene plays a more important role in the genesis of the metabolic acidosis than was previously believed. This conclusion is supported by the observation that the rate of excretion of ammonium was not low during metabolic acidosis in six of eight patients, suggesting that distal renal tubular acidosis was not an important acid-base abnormality in most cases where ammonium was measured. The excretion of hippurate in the urine unmatched by ammonium also mandates an enhanced rate of excretion of the cations, sodium and potassium. The loss of sodium causes extracellular fluid volume contraction and a fall in the glomerular filtration rate, which may transform the normal anion gap type of metabolic acidosis into one with a high anion gap (accumulation of hippurate and other anions). Continuing loss of potassium in the urine leads to hypokalemia. An understanding of the metabolism of toluene provides the basis for the unusual biochemical abnormalities seen with abuse of this solvent.
Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia
Authors: Alejandro Gutierrez, Ruta Grebliunaite, Hui Feng, Elena Kozakewich, Shizhen Zhu, Feng Guo, Elspeth Payne, Marc Mansour, Suzanne E. Dahlberg, Donna S. Neuberg, Jeroen den Hertog, Edward V. Prochownik, Joseph R. Testa, Marian Harris, John P. Kanki, A. Thomas Look
Journal: The Journal of Experimental Medicine (2011)

The MYC oncogenic transcription factor is overexpressed in most human cases of T cell acute lymphoblastic leukemia (T-ALL), often downstream of mutational NOTCH1 activation. Genetic alterations in the PTEN–PI3K–AKT pathway are also common in T-ALL. We generated a conditional zebrafish model of T-ALL in which 4-hydroxytamoxifen (4HT) treatment induces MYC activation and disease, and withdrawal of 4HT results in T-ALL apoptosis and tumor regression. However, we found that loss-of-function mutations in zebrafish pten genes, or expression of a constitutively active Akt2 transgene, rendered tumors independent of the MYC oncogene and promoted disease progression after 4HT withdrawal. Moreover, MYC suppresses pten mRNA levels, suggesting that Akt pathway activation downstream of MYC promotes tumor progression. Our findings indicate that Akt pathway activation is sufficient for tumor maintenance in this model, even after loss of survival signals driven by the MYC oncogene.
Oral amoxicillin compared with injectable procaine benzylpenicillin plus gentamicin for treatment of neonates and young infants with fast breathing when referral is not possible: a randomised, open-label, equivalence trial
Authors: Antoinette Tshefu, Adrien Lokangaka, Serge Ngaima, Cyril Engmann, Fabian Esamai, Peter Gisore, Adejumoke Idowu Ayede, Adegoke Gbadegesin Falade, Ebunoluwa A Adejuyigbe, Chineme Henry Anyabolu, Robinson D Wammanda, Clara L Ejembi, William N Ogala, Lu Gram, Simon Cousens
Journal: The Lancet (2015)
Merger with AstraZeneca will create a scientific "powerhouse," says Pfizer
Authors: A. O'Dowd
Journal: BMJ (2014)

Concerns among scientists about a possible takeover of AstraZeneca by the giant US drug company Pfizer will be dealt with, MPs have been told.

Pfizer representatives, appearing before the House of Commons Science and Technology Committee on 14 May, said that the company wanted to convince the scientific professions and the United Kingdom that a merger of the two companies would create a “powerhouse” of science for the benefit of patients.

The MPs, holding an inquiry into the possible AstraZeneca takeover,1 said that UK scientific organisations had expressed concern about the possible bid and asked whether Pfizer had held any discussions with them.

Mikael Dolsten, president for worldwide research and development at Pfizer, …
FRI0097 Comparative effectiveness and time to response among adalimumab, abatacept, etanercept, infliximab and rituximab in a real world routine care registry
Authors: Y. Yazici, A.L. Regens, C.J. Swearingen
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> With the availability of multiple biologic agents, with different modes of action, and no head to head trials, it is of use to examine comparative effectiveness of these agents in real world registries to inform physicians how they might be used for the treatment of rheumatoid arthritis. <h3>Objectives</h3> To compare time to response and efficacy among biologic agents. <h3>Methods</h3> Usage of the biologic medications abatacept, adalimumab, etanercept,infliximab and rituximab along with self-reported disease activity and clinic measures were abstracted from ARMD registry at NYU. Time to first response defined as an improvement in RAPID3 of at least 3.6 was calculated; change from biologic medication initiation to first response for self-reported disease activity and clinic measures was estimated. Differences in time to first response between biologic medications were estimated using Cox proportional hazards model. <h3>Results</h3> 4299 encounteres were reviewed for this analysis. A total of 526 treatment courses were determined. 406 of 526 courses represent the first biologic medication used by an individual; 88 individuals used two biologic medications at different times, while 26 had used three biologics, and 6 had used 4. Abatacept had more patients achieve response (66%) characterized by a reduction in RAPID of 3.6 points or greater than adalimumab (63%), etanercept (61%), infliximab (43%), rituximab (41%) although this difference was not statistically siginficant. Increased age and increased duration of disease were associated with decreased likelihood of achieving a RAPID3 reponse. Time to reponse in the first 6 months after treatment was not significantly different among any of the biologics (Fig. 1). <h3>Conclusions</h3> No differences in efficacy and time to response among adalimumab, abatacept, etanercept, infliximab or rituximab in the first 6 months after RA treatment was initiated were noted. With no difference in clinical outcomes, most treatment decisions may be based on ease of use and safety data of respective biologics agents when they are being considered for RA treatment. <h3>Disclosure of Interest</h3> Y. Yazici Grant/Research support from: Abbott, BMS, Celgene, Genentech, Consultant for: Abbott, BMS, Centocor, Celgene, Pfizer, genentech, UCB, Takeda, A. Regens: None Declared, C. Swearingen: None Declared
Using Lidocaine and Benzocaine to Link Sodium Channel Molecular Conformations to State-Dependent Antiarrhythmic Drug Affinity
Authors: Dorothy A. Hanck, Elena Nikitina, Megan M. McNulty, Harry A. Fozzard, Gregory M. Lipkind, Michael F. Sheets
Journal: Circulation Research (2009)

Lidocaine and other antiarrhythmic drugs bind in the inner pore of voltage-gated Na channels and affect gating use-dependently. A phenylalanine in domain IV, S6 (Phe1759 in Na(V)1.5), modeled to face the inner pore just below the selectivity filter, is critical in use-dependent drug block.Measurement of gating currents and concentration-dependent availability curves to determine the role of Phe1759 in coupling of drug binding to the gating changes.The measurements showed that replacement of Phe1759 with a nonaromatic residue permits clear separation of action of lidocaine and benzocaine into 2 components that can be related to channel conformations. One component represents the drug acting as a voltage-independent, low-affinity blocker of closed channels (designated as lipophilic block), and the second represents high-affinity, voltage-dependent block of open/inactivated channels linked to stabilization of the S4s in domains III and IV (designated as voltage-sensor inhibition) by Phe1759. A homology model for how lidocaine and benzocaine bind in the closed and open/inactivated channel conformation is proposed.These 2 components, lipophilic block and voltage-sensor inhibition, can explain the differences in estimates between tonic and open-state/inactivated-state affinities, and they identify how differences in affinity for the 2 binding conformations can control use-dependence, the hallmark of successful antiarrhythmic drugs.
Pulmonary Edema and Propoxyphene
Authors: Vincent J. M. DiMaio
Journal: JAMA (1971)

<h3>To the Editor.—</h3> The article "Pulmonary Edema Associated with Propoxyphene Intoxicition" (<b>215</b>:259-262, 1971), described the phenomenon of acute pulmonary edema, congestion, and hemorrhage that is seen daily in all manners of death by the forensic pathologist. These deaths range from sudden death due to cardiac arrhythmias, to barbiturate overdose, to gunshot wounds. The finding of pulmonary congestion, edema, and hemorrhage is in our opinion a nonspecific phenomenon due to terminal hypoxia, and can be found in all types of acute deaths.
Endothelium-derived Toll-like receptor-4 is the key molecule in LPS-induced neutrophil sequestration into lungs
Authors: Graciela Andonegui, Claudine S. Bonder, Francis Green, Sarah C. Mullaly, Lori Zbytnuik, Eko Raharjo, Paul Kubes
Journal: Journal of Clinical Investigation (2003)

The rapid and selective accumulation of neutrophils into the lungs is thought to underlie the pulmonary failure that leads to sepsis-related death. In this study we investigated whether neutrophil TLR4 is important in LPS-induced pulmonary neutrophil recruitment by creating chimeric mice (transferring bone marrow between TLR4(+/+) and TLR4(-/-) mice). In TLR4(+/+) mice receiving TLR4(-/-) bone marrow, 6 weeks after transplant TLR4 was absent in all circulating leukocytes as well as in resident macrophages (these mice were termed LeukocyteTLR4(-/-)), and these cells were completely nonresponsive to LPS. In TLR4(-/-) mice receiving TLR4(+/+) bone marrow, endothelial cells but not leukocytes were deficient in TLR4 (EndotheliumTLR4(-/-)). Surprisingly, systemic LPS (0.5 mg/kg) induced a dramatic increase in neutrophil sequestration into the lungs of LeukocyteTLR4(-/-) mice over the first 4 hours. Concomitantly, numbers of circulating leukocytes decreased by 90%. By contrast, EndotheliumTLR4(-/-) mice showed very little increase in neutrophil sequestration in the lungs, suggesting that endothelium rather than leukocyte TLR4 was important. Intravital microscopy of peripheral microcirculation in the cremaster muscle revealed about 30-fold more leukocyte-endothelial cell interactions in LPS-treated EndotheliumTLR4(-/-) mice than in LPS-treated LeukocyteTLR4(-/-) mice. This is consistent with less sequestration of leukocytes into the lungs of EndotheliumTLR4(-/-) mice. In conclusion, our data challenge the view that LPS directly activates neutrophils to trap in lungs and suggest a far more important role than previously appreciated for the endothelial cells.
Studies on manganese
Authors: John P. Mahoney, Walter J. Small
Journal: Journal of Clinical Investigation (1968)

The biological half-life of manganese and some factors influencing it have been studied in man. The disappearance of manganese from the body in normal subjects is described by a curve having two exponential components. An average of 70% of the injected material was eliminated by the "slow" pathway. The half-time characterizing this component showed a small variation in normal subjects and had an average value of 39 days. The half-time for the "fast" component also showed a small variation and had an average value of 4 days.