tbuckley/cabot-search huggingface dataset:
Nitroxide radical attenuates ischaemia/reperfusion injury to the rat small intestine
Authors: R Udassin, Y Haskel, A Samuni
Journal: Gut (1998)

Background —Free radicals are associated with post-ischaemic intestinal injury and contribute to major clinical problems primarily in premature infants. Various antioxidative means and modes of intervention, previously tested, have demonstrated only limited efficacy. Aims —To study the protective activity of the stable nitroxide radical 4-OH, 2,2,6,6-tetramethylpiperidine-1-oxyl (TPL) and its respective hydroxylamine (TPL-H) against ischaemia/reperfusion (I/R) injury. Methods —An isolated loop of ileum was created in laboratory male Sabra rats and constantly perfused with warmed normal saline. Intestinal injury was elicited through clamping of the superior mesenteric rat artery followed by reperfusion. Either TPL or TPL-H was given intravenously immediately before ischaemia or reperfusion and continuously afterwards. The rate of mucosal to lumen clearance of para-aminohippurate (PAH) was used to evaluate intestinal mucosal injury. Serum and perfusate levels of both TPL and TPL-H were measured using electron paramagnetic resonance spectrometry. Results —The increase in intestinal permeability induced by I/R was significantly inhibited by both TPL and TPL-H. The nitroxide was effective also when given immediately before reperfusion. Conclusion —Through a continuous exchange, TPL and TPL-H act as self-replenishing antioxidants and thus protect from intestinal injury. This demonstrates the potential of the family of nitroxide antioxidants against oxidative stress in general and I/R injury in particular.
Gallstones in cystic fibrosis: A critical reappraisal
Authors: Mario Angelico, Claudia Gandin, Pietro Canuzzi, Serenella Bertasi, Alfredo Cantafora, Adriano de Santis, Serena Quattrucci, Mariano Antonelli
Journal: Hepatology (1991)

Radiolucent gallstones are common in young adults with cystic fibrosis. In the mid-1970s, it was suggested that gallstones are made of cholesterol, but this hypothesis has never been tested. Several recent studies have shown that the detection of cholesterol monohydrate crystals in bile has high sensitivity and specificity for the diagnosis of cholesterol gallstones. We therefore used this approach to study 17 young adults with cystic fibrosis, 10 of whom had radiolucent gallstones. The two groups of patients were comparable in age and gender (all patients but one were male). Duodenal bile was obtained after gallbladder contraction with intravenous cerulein; it was used for lipid and protein chemistry studies and for polarizing microscopy. The latter was performed both in whole bile and in the postultracentrifugation (100,000 g ) sediment. Bile cholesterol saturation did not significantly differ between patients with (1.21 ± 0.28) or without gallstones (0.99 ± 0.54). Slight cholesterol supersaturation was found in 7 of 10 gallstone and three of seven nongallstone patients. At no time were cholesterol crystals detected in either the group, even after bile ultracentrifugation. Two more cystic fibrosis patients with gallstones died of severe bronchopneumopathy, and small pigment gallstones were obtained at autopsy. At stone analysis, cholesterol content was 44% and 28% of dry weight, respectively. Infrared spectroscopy of stone powder was compatible with the presence of calcium bilirubinate and proteins as major components. We conclude that radiolucent gallstones of cystic fibrosis are not of the conventional cholesterol type. (Hepatology 1991;14:768-775).
THE INTERNEURONIC SYNAPSE IN DISEASE
Authors: B. H. Shaw
Journal: BMJ (1913)

MEDICAL JOURNAL of May 3rd. ; I have many times, in common with other surgeons,-*operated upon cases of chronic rheumatic arthritis to relieve pain and deformity, but as my last case is identical in all essential respects with the two cases described in the communication, and as the operation was performed on the patient's hip on October 22nd last, three months before Mr. Sampson Handley operated upon his first patient, it may be of interest to mention the outstanding features, and tllus put a third case on record.The question of priority is of no great importance, but Mr. Sampson Handleyand Dr. Preston Ball are in error in thinking that the operation had not been performed prior to their first case in January, 1913.Miss H. D., aged 21, residing in London, was sent to me in September last, the subject of polyarticular chronic rheumatic arthritis from whiclh she had suffered from childhood.The left knee-joint, the right hip and the two wrists were disorganized with the changes characteristic of the disease.The left knee could not be completely extended without intense pain, and the right hip could bear no weight whatever, the slightest pressure on the
Spirometry in young children: should computer-animation programs be used during testing?
Authors: V. Gracchi, M. Boel, J. van der Laag, C.K. van der Ent
Journal: European Respiratory Journal (2003)

Currently, computer-animation programs are frequently used to instruct and stimulate young children in performing maximal expiratory flow/volume (MEFV) curves. The reproducibility and maximal performance of MEFV manoeuvres with and without the use of two computer-animation programs (the “candles” and the “balloon” programs) were evaluated. Eighty-eight children, aged 4–8 yrs, were randomly assigned to one of the two animation programs. All children performed two series of at least three technically acceptable curves, one series with the incentive and one without, in random order. With the use of computer-animation programs, a lower proportion of children were able to fulfil international criteria for forced vital capacity (FVC) and forced expiratory volume in one second (FEV 1 ) reproducibility. The use of incentives improved reproducibility and performance of peak expiratory flow (PEF). Performance of FVC decreased significantly in 6–8‐yr-old children using the animation programs. Training with a program for a short period of time before the formal lung-function test may be valuable. According to the results, however, the use of these programs during tests under the guidance of an experienced lung-function technician cannot be routinely recommended because of possible deteriorating effects on reproducibility and performance of forced expiratory manoeuvres.
Cell-cycle regulated transcription associates with DNA replication timing in yeast and human
Authors: Hunter B Fraser
Journal: Genome biology (2013)

Eukaryotic DNA replication follows a specific temporal program, with some genomic regions consistently replicating earlier than others, yet what determines this program is largely unknown. Highly transcribed regions have been observed to replicate in early S-phase in all plant and animal species studied to date, but this relationship is thought to be absent from both budding yeast and fission yeast. No association between cell-cycle regulated transcription and replication timing has been reported for any species. Here I show that in budding yeast, fission yeast, and human, the genes most highly transcribed during S-phase replicate early, whereas those repressed in S-phase replicate late. Transcription during other cell-cycle phases shows either the opposite correlation with replication timing, or no relation. The relationship is strongest near late-firing origins of replication, which is not consistent with a previously proposed model—that replication timing may affect transcription—and instead suggests a potential mechanism involving the recruitment of limiting replication initiation factors during S-phase. These results suggest that S-phase transcription may be an important determinant of DNA replication timing across eukaryotes, which may explain the well-established association between transcription and replication timing.
Effects of Drug Loading on the Antitumor Activity of a Monoclonal Antibody Drug Conjugate
Authors: Kevin J. Hamblett, Peter D. Senter, Dana F. Chace, Michael M. C. Sun, Joel Lenox, Charles G. Cerveny, Kim M. Kissler, Starr X. Bernhardt, Anastasia K. Kopcha, Roger F. Zabinski, Damon L. Meyer, Joseph A. Francisco
Journal: Clinical Cancer Research (2004)

An antibody-drug conjugate consisting of monomethyl auristatin E (MMAE) conjugated to the anti-CD30 monoclonal antibody (mAb) cAC10, with eight drug moieties per mAb, was previously shown to have potent cytotoxic activity against CD30(+) malignant cells. To determine the effect of drug loading on antibody-drug conjugate therapeutic potential, we assessed cAC10 antibody-drug conjugates containing different drug-mAb ratios in vitro and in vivo.Coupling MMAE to the cysteines that comprise the interchain disulfides of cAC10 created an antibody-drug conjugate population, which was purified using hydrophobic interaction chromatography to yield antibody-drug conjugates with two, four, and eight drugs per antibody (E2, E4, and E8, respectively). Antibody-drug conjugate potency was tested in vitro against CD30(+) lines followed by in vivo xenograft models. The maximum-tolerated dose and pharmacokinetic profiles of the antibody-drug conjugates were investigated in mice.Although antibody-drug conjugate potency in vitro was directly dependent on drug loading (IC(50) values E8<E4<E2), the in vivo antitumor activity of E4 was comparable with E8 at equal mAb doses, although the E4 contained half the amount of MMAE per mAb. E2 was also an active antitumor agent but required higher doses. The maximum-tolerated dose of E2 in mice was at least double that of E4, which in turn was twice that of E8. MMAE loading affected plasma clearance, as E8 cleared 3-fold faster than E4 and 5-fold faster than E2.By decreasing drug loading per antibody, the therapeutic index was increased demonstrating that drug loading is a key design parameter for antibody-drug conjugates.
Evaluation of Prime/Boost Regimens Using Recombinant Poxvirus/Tyrosinase Vaccines for the Treatment of Patients with Metastatic Melanoma
Authors: Kimberly R. Lindsey, Linda Gritz, Richard Sherry, Andrea Abati, Patricia A. Fetsch, Lisa C. Goldfeder, Monica I. Gonzales, Kimberly A. Zinnack, Linda Rogers-Freezer, Leah Haworth, Sharon A. Mavroukakis, Donald E. White, Seth M. Steinberg, Nicholas P. Restifo, Dennis L. Panicali, Steven A. Rosenberg, Suzanne L. Topalian
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Two clinical trials were conducted to evaluate the clinical efficacy and immunologic impact of vaccination against the tyrosinase protein plus systemic interleukin 2 (IL-2) administration in patients with advanced metastatic melanoma. Experimental Design: Full-length tyrosinase was employed as an immunogen to induce diverse immunologic responses against a commonly expressed melanoma antigen. Heterologous prime/boost vaccination with recombinant vaccinia and fowlpox vectors encoding tyrosinase was first explored in a randomized three-arm phase II trial, in which vaccines were administered alone or concurrently with low-dose or high-dose IL-2. In a subsequent single cohort phase II trial, all patients received the same vaccines and high-dose IL-2 sequentially rather than concurrently. Results: Among a total of 64 patients treated on these trials, 8 objective partial responses (12.5%) were observed, all in patients receiving high-dose IL-2. Additional patients showed evidence of lesional regression (mixed tumor response) or overall regression that did not achieve partial response status (minor response). In vitro evidence of enhanced immunity against tyrosinase following protocol treatments was documented in 3 of 49 (6%) patients tested serologically, 3 of 23 (13%) patients tested for T-cell recognition of individual tyrosinase peptides, and 4 of 16 (25%) patients tested for T-cell recognition of full-length tyrosinase protein with real-time reverse transcription-PCR techniques. Conclusions: Whereas prime/boost immunization with recombinant vaccinia and fowlpox viruses enhanced antityrosinase immunity in some patients with metastatic melanoma, it was ineffective alone in mediating clinical benefit, and in combination with IL-2 did not mediate clinical benefit significantly different from that expected from treatment with IL-2 alone.
Comparison of 99mTc-DTPA and urea for measuring cefepime concentrations in epithelial lining fluid
Authors: S. Bayat, K. Louchahi, B. Verdière, D. Anglade, A. Rahoui, P‐M. Sorin, M. Tod, O. Petitjean, F. Fraisse, F.A. Grimbert
Journal: European Respiratory Journal (2004)

The efficacy of antimicrobial agents against pulmonary infections depends on their local concentrations in the lung. The aims of the present study were to: 1) compare technetium‐99m diethylenetriaminepenta-acetic acid ( 99m Tc‐DTPA) and urea as markers of epithelial lining fluid (ELF) dilution for measuring ELF concentrations of pharmaceuticals; 2) quantify ELF cefepime concentrations in normal and injured lung; and 3) measure the increase in permeability to cefepime following oleic acid-induced acute lung injury. A modified bronchoalveolar lavage technique, based on equilibration of infused 99m Tc-DTPA, was used to measure ELF volume. Cefepime was administered intravenously at steady plasma levels. Six serial bronchoalveolar lavages were performed 5 h after the beginning of infusion. ELF to plasma cefepime concentration ratios were 95±17 and 100±14.5% in normal and injured lung respectively. When urea was used as marker, cefepime concentration ratios were underestimated at 16.4±2.7 and 73.9±8.4% respectively. Cefepime blood/airspace clearance increased from 3.8±0.7 µL·min −1 in controls to 39.8±4.9 µL·min −1 in acute lung injury. It was concluded that: 1) cefepime concentrations in epithelial lining fluid were in equilibrium with those in plasma in both normal and injured lung after 5 h at steady plasma concentrations; 2) epithelial lining fluid cefepime concentration by the urea method was much less underestimated in injured versus normal lung; and 3) acute lung injury induces a 10‐fold elevation of cefepime blood/airspace clearance.
Effects of mandibular advancement on airway curvature and obstructive sleep apnoea severity
Authors: S. Tsuiki, A.A. Lowe, F.R. Almeida, N. Kawahata, J.A. Fleetham
Journal: European Respiratory Journal (2004)

In a curved tube, the amount of airflow appears to be influenced by the amount of curvature. The purpose of this study was to investigate changes in obstructive sleep apnoea (OSA) severity and awake velopharyngeal curvature in response to an anteriorly titrated mandibular position in 20 male OSA patients. Baseline supine cephalometry was obtained before the initial insertion of a titratable oral appliance and follow-up supine cephalometry was undertaken after titration of the mandibular position with the appliance in place. The mean apnoea/hypopnea index (AHI) before treatment (31.6±13.0 events·h −1 ) was significantly reduced (9.8±7.4 events·h −1 ) after titration of the mandibular position in all 20 patients. There was a significant increase in the anteroposterior calibre and the radius of the curvature of the anterior wall of the velopharynx in 14 good responders who exhibited an AHI reduction to ≤15. Similar observations were not found in six poor responders. To conclude, an anteriorly titrated mandibular position reduced obstructive sleep apnoea severity, enlarged the velopharynx and diminished the curvature of the anterior velopharyngeal wall in good responders. It is proposed that this change in the upper airway curvature associated with mandibular advancement may effect obstructive sleep apnoea severity through its effect on airflow dynamics.
A prospective multicenter phase II study of oral and i.v. vinorelbine plus trastuzumab as first-line therapy in HER2-overexpressing metastatic breast cancer
Authors: V. Heinemann, D. Di Gioia, U. Vehling-Kaiser, H.-D. Harich, B. Heinrich, A. Welt, C. Ziske, G. Deutsch, R. Pihusch, H. Kölbl, S. Hegewisch-Becker, M. Michl, H.J. Stemmler
Journal: Annals of Oncology (2010)
Phosphorylation of histone deacetylase 7 by protein kinase D mediates T cell receptor–induced Nur77 expression and apoptosis
Authors: Franck Dequiedt, Johan Van Lint, Emily Lecomte, Viktor Van Duppen, Thomas Seufferlein, Jackie R. Vandenheede, Ruddy Wattiez, Richard Kettmann
Journal: The Journal of Experimental Medicine (2005)

The molecular basis of thymocyte negative selection, a crucial mechanism in establishing central tolerance, is not yet resolved. Histone deacetylases (HDACs) have emerged as key transcriptional regulators in several major developmental programs. Recently, we showed that the class IIa member, HDAC7, regulates negative selection by repressing expression of Nur77, an orphan nuclear receptor involved in antigen-induced apoptosis of thymocytes. Engagement of the T cell receptor (TCR) alleviates this repression through phosphorylation-dependent nuclear exclusion of HDAC7. However, the identity of the TCR-activated kinase that phosphorylates and inactivates HDAC7 was still unknown. Here, we demonstrate that TCR-induced nuclear export of HDAC7 and Nur77 expression is mediated by activation of protein kinase D (PKD). Indeed, active PKD stimulates HDAC7 nuclear export and Nur77 expression. In contrast, inhibition of PKD prevents TCR-mediated nuclear exclusion of HDAC7 and associated Nur77 activation. Furthermore, we show that HDAC7 is an interaction partner and a substrate for PKD. We identify four serine residues in the NH2 terminus of HDAC7 as targets for PKD. More importantly, a mutant of HDAC7 specifically deficient in phosphorylation by PKD, inhibits TCR-mediated apoptosis of T cell hybridomas. These findings indicate that PKD is likely to play a key role in the signaling pathways controlling negative selection.
Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial
Authors: Stefano Cascinu, Rossana Berardi, Roberto Labianca, Salvatore Siena, Alfredo Falcone, Enrico Aitini, Sandro Barni, Francesco Di Costanzo, Elisa Dapretto, Giuseppe Tonini, Chiara Pierantoni, Salvatore Artale, Silvia Rota, Irene Floriani, Mario Scartozzi, Alberto Zaniboni
Journal: The Lancet Oncology (2008)
A YAC Mouse Model for Huntington’s Disease with Full-Length Mutant Huntingtin, Cytoplasmic Toxicity, and Selective Striatal Neurodegeneration
Authors: J.Graeme Hodgson, Nadia Agopyan, Claire-Anne Gutekunst, Blair R Leavitt, Fred LePiane, Roshni Singaraja, Desmond J Smith, Nagat Bissada, Krista McCutcheon, Jamal Nasir, Laure Jamot, Xiao-Jiang Li, Mary E Stevens, Erica Rosemond, John C Roder, Anthony G Phillips, Edward M Rubin, Steven M Hersch, Michael R Hayden
Journal: Neuron (1999)
Increased Blood Glucose and Insulin, Body Size, and Incident Colorectal Cancer
Authors: R E Schoen, C M Tangen, L H Kuller, G L Burke, M Cushman, R P Tracy, A Dobs, P J Savage
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: Abdominal obesity—an elevated level of visceral adipose tissue—has been linked to colorectal cancer. Furthermore, elevated levels of visceral adipose tissue have been associated with hyperinsulinemia, and insulin is a growth factor in the colon. We assessed whether waist circumference, a surrogate measure of visceral adipose tissue, and metabolic parameters associated with visceral adipose tissue were related to colorectal cancer. METHODS: In the Cardiovascular Health Study cohort, we examined the relationship of baseline measurements of body size, glucose, insulin, and lipoproteins to incident colorectal cancer. All P values are two-sided. RESULTS: Among 5849 participants, 102 incident cases of colorectal cancer were identified. Individuals in the highest quartile of fasting glucose had a nearly twofold increased risk of colorectal cancer (relative risk [RR] = 1.8; 95% confidence interval [CI] = 1.0-3.1), and the linear trend RR (LT RR = 1.2; 95% CI = 1.0-1.5) for fasting glucose level was statistically significant ( P = .02). Glucose and insulin levels 2 hours after oral glucose challenge also exhibited statistically significant associations with colorectal cancer (2-hour glucose levels: RR = 2.4 [95% CI = 1.2-4.7]/LT RR = 1.3 [95% CI = 1.0-1.6; P = .02]; 2-hour insulin levels: RR = 2.0 [95% CI = 1.0-3.8]/LT RR = 1.2 [ 95% CI = 1.0-1.5; P = .04]). Analysis of fasting insulin levels suggested a threshold effect, with values above the median associated with colorectal cancer (RR = 1.6; 95% CI = 1.1-2.4; P = .02). Higher levels of waist circumference were also statistically significantly associated with colorectal cancer (RR = 1.9; 95% CI = 1.1-3.3; P = .02). CONCLUSIONS: These data provide, to our knowledge, the first direct evidence of an association between elevated visceral adipose tissue level, its associated metabolic effects, and colorectal cancer.
Hypotension, lipodystrophy, and insulin resistance in generalized PPARγ-deficient mice rescued from embryonic lethality
Authors: Sheng Zhong Duan, Christine Y. Ivashchenko, Steven E. Whitesall, Louis G. D’Alecy, Damon C. Duquaine, Frank C. Brosius, Frank J. Gonzalez, Charles Vinson, Melissa A. Pierre, David S. Milstone, Richard M. Mortensen
Journal: Journal of Clinical Investigation (2007)

We rescued the embryonic lethality of global PPARgamma knockout by breeding Mox2-Cre (MORE) mice with floxed PPARgamma mice to inactivate PPARgamma in the embryo but not in trophoblasts and created a generalized PPARgamma knockout mouse model, MORE-PPARgamma knockout (MORE-PGKO) mice. PPARgamma inactivation caused severe lipodystrophy and insulin resistance; surprisingly, it also caused hypotension. Paradoxically, PPARgamma agonists had the same effect. We showed that another mouse model of lipodystrophy was hypertensive, ruling out the lipodystrophy as a cause. Further, high salt loading did not correct the hypotension in MORE-PGKO mice. In vitro studies showed that the vasculature from MORE-PGKO mice was more sensitive to endothelial-dependent relaxation caused by muscarinic stimulation, but was not associated with changes in eNOS expression or phosphorylation. In addition, vascular smooth muscle had impaired contraction in response to alpha-adrenergic agents. The renin-angiotensin-aldosterone system was mildly activated, consistent with increased vascular capacitance or decreased volume. These effects are likely mechanisms contributing to the hypotension. Our results demonstrated that PPARgamma is required to maintain normal adiposity and insulin sensitivity in adult mice. Surprisingly, genetic loss of PPARgamma function, like activation by agonists, lowered blood pressure, likely through a mechanism involving increased vascular relaxation.