tbuckley/cabot-search huggingface dataset:
A Phase I-II Study to Determine the Maximum Tolerated Infusion Rate of Rituximab with Special Emphasis on Monitoring the Effect of Rituximab on Cardiac Function
Authors: Marco Siano, Erika Lerch, Laura Negretti, Emanuele Zucca, Delvys Rodriguez-Abreu, Michel Oberson, Leda Leoncini, Oreste Mora, Cristiana Sessa, Augusto Gallino, Michele Ghielmini
Journal: Clinical Cancer Research (2008)

Abstract Purpose: This phase I infusion rate escalation trial was undertaken to evaluate the maximum applicable infusion rate for rituximab without steroid premedication in patients having received one previous rituximab infusion. Experimental Design: Cohorts of at least three patients were assigned to rituximab with or without concomitant chemotherapy. The initial infusion rate was 200 mg/h in the first cohort, and was increased by 100 mg/h in each subsequent cohort to a maximum of 700 mg/h. In each patient the infusion rate was increased by 100 mg/h every 30 minutes to the total dose (375 mg/m2). In the first six cohorts (21 patients), two well-tolerated rituximab administrations were required; in the 7th cohort (11 patients) one previously well-tolerated rituximab infusion was required. Patients did not receive steroid premedication and were monitored with electrocardiograms (ECG), echocardiograms, Holter ECGs, troponin, and brain natriuretic peptide (BNP). Results: Thirty-two patients were included and 128 cycles were done, 85 at a rate of 700 mg/h. Patients tolerated infusion rates without major side effects. There were no new clinically relevant ECG alterations. Troponin (&amp;lt; 0.1 ng/L) and mean cardiac ejection fraction (65%) remained in the reference range; BNP baseline level increased significantly 24 hours after rituximab administration (from 30.4 to 64.1 ng/L; P &amp;lt; 0.0001). Conclusions: Rituximab can be administered safely at 700 mg/h without steroid premedication in patients having received at least one rituximab dose in the previous 3 months.
Epidemiology and clinical practice.
Authors: S S Bakhshi
Journal: BMJ (1980)

you say in your leading article (24 May, p 1240), but absolutely vital.In fact, high-titre antibodies to pseudomonas, in particular to exotoxin A (and lipid A), provide very good protection even in patients who are neutro- penic or who have serious underlying diseases, as reported by Pollack and Young.'Why was this essential reference not quoted ?Taken in conjunction with the vaccine production work of Jones et al2 it really is the promise for the future.Similar principles apply to other Gram-negative infections.
Relaxation of Functional Constraint on Light-Independent Protochlorophyllide Oxidoreductase in Thuja
Authors: Junko Kusumi, Aya Sato, Hidenori Tachida
Journal: Molecular Biology and Evolution (2006)

The light-independent protochlorophyllide oxidoreductase (DPOR) plays a key role in the ability of nonflowering plants and algae to synthesize chlorophyll in darkness. This enzyme consists of three subunits encoded by the chlB, chlL, and chlN genes in the plastid genome. Previously, we found a high nonsynonymous substitution rate (dN) of the chlL gene in the lineage of Thuja standishii, a conifer belonging to the Cupressaceae. Here we revealed that the acceleration of dN in the chlL occurred as well in other species of Thuja, Thuja occidentalis and Thuja plicata. In addition, dark-grown seedlings of T. occidentalis were found to exhibit a pale yellowish color, and their chlorophyll concentration was much lower than that of other species of Cupressaceae. The results suggested that the species of Thuja have lost the ability to synthesize chlorophyll in darkness, and the functional constraint on the DPOR would thus be expected to be relaxed in this genus. Therefore, we expected to find that the evolutionary rates of all subunits of DPOR would in this case be accelerated. Sequence analyses of the chlN and chlB (encoding the other subunits of DPOR) in 18 species of Cupressaceae revealed that the dN of the chlN gene was accelerated in Thuja as was the dN of the chlL gene, but the dN of the chlB gene did not appear to differ significantly among the species of Cupressaceae. Sequencing of reverse transcription–polymerase chain reaction (RT-PCR) products of these genes showed that RNA editing was rare and unlikely to have contributed to the acceleration. Moreover, the RT-PCR analysis indicated that all chl genes were still transcriptionally active in T. occidentalis. Based on these results, it appears that species of Thuja still bear the DPOR protein, although the enzyme has lost its activity because of nonsynonymous mutations of some of the chl genes. The lack of acceleration of the dN of the chlB gene might be accounted for by various unknown functions of its gene product.
How to assess your learning needs
Authors: K. Walsh
Journal: Journal of the Royal Society of Medicine (2005)

When was the last time that you assessed your learning needs? Or does the term mean nothing to you at all? Maybe you are a consultant of long standing and feel that you should be free to learn what you want to learn and not what you are told to learn. Perhaps you are a foundation-year doctor and think that you only need to cover the foundation year's curriculum. These views are reasonable but there are many reasons why we should spend some time thinking about our learning needs.
A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans
Authors: Akihisa Sawada, Yoshihiro Takihara, Ji Yoo Kim, Yoshiko Matsuda-Hashii, Sadao Tokimasa, Hiroyuki Fujisaki, Keiko Kubota, Hiroko Endo, Takashi Onodera, Hideaki Ohta, Keiichi Ozono, Junichi Hara
Journal: Journal of Clinical Investigation (2003)

A girl with congenital agammaglobulinemia and minor facial anomalies lacked B cells in peripheral blood: karyotypic analysis of white blood cells showed balanced translocation, t(9;20)(q33.2;q12). In the current study, we isolated a novel gene, leucine-rich repeat–containing 8 (LRRC8), at the translocation site on chromosome 9. It has four transmembrane helixes with one isolated and eight sequentially located leucine-rich repeats (LRRs) and constitutes a new protein family. It is expressed on T cells as well as on B-lineage cells. Translocation truncates the LRRC8 gene, resulting in deletion of the eighth, ninth, and half of the seventh LRR domains located close to the C-terminal. The truncated form of the LRRC8 gene is transcribed with sequences from the noncoding region adjacent to the truncated seventh LRR. Protein products derived from the truncated gene are coexpressed on white blood cells with the intact LRRC8 protein from the untranslocated allele. Transplantation experiments with murine bone marrow cells that were forced to express the truncated LRRC8 show that expression of the truncated protein inhibited B cell development. These results indicate that LRRC8 is responsible for the B cell deficiency in this patient and is required for B cell development.
RETRACTED: Suppressors of Cytokine Signaling 2 and 3 Diametrically Control Macrophage Polarization
Authors: Shaun Spence, Amy Fitzsimons, Caroline R. Boyd, Julia Kessler, Denise Fitzgerald, Joanne Elliott, Joan Ní Gabhann, Siobhan Smith, Antonio Sica, Emily Hams, Sean P. Saunders, Caroline A. Jefferies, Padraic G. Fallon, Danny F. McAuley, Adrien Kissenpfennig, James A. Johnston
Journal: Immunity (2012)
Natural Killer Cytotoxic Factor Induction by K562 Cells in Patients With Advanced Cancer: Correlation With Production of Interferon&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: E H Steinhauer, A T Doyle, J Reed, A S Kadish
Journal: JNCI Journal of the National Cancer Institute (1985)

Advanced cancer patients were studied for their ability to produce natural killer cytotoxic factor (NKCF). Of 23 patients with advanced epithelial cancers, 8 showed deficient natural killer (NK) activity, as measured in a standard 51Cr release assay. Lymphocytes from these patients did not generate NKCF (nonproducers) in the presence of K562 cells. In addition, 7 other patients whose NK activity was in the normal range did not generate NKCF. Thus the deficiency in NKCF production was only partially correlated with the level of NK activity. Supernatants generated for NKCF were also assayed for antiviral activity. Mean interferon (IFN) titer of supernatants generated from peripheral blood lymphocytes (PBL) of cancer patients was significantly lower than that of supernatants generated by PBL from normal donors. Supernatants from 10 of 15 NKCF nonproducers contained no detectable IFN, whereas the remaining 5 contained up to 100 U IFN. NKCF was never generated in the absence of IFN. The defect in NKCF production by PBL from cancer patients could be corrected by the incubation of effector cells with exogenous IFN-alpha or IFN-alpha inducers, such as other tumor cells or viruses. The relationship among NKCF, IFN, and NK activities is discussed.
THE MOLECULES OF MECHANOSENSATION
Authors: Jaime García-Añoveros, David P. Corey
Journal: Annual Review of Neuroscience (1997)

▪ Abstract Mechanosensation, the transduction of mechanical forces into a cellular electrochemical signal, enables living organisms to detect touch; vibrations, such as sound; accelerations, including gravity; body movements; and changes in cellular volume and shape. Ion channels directly activated by mechanical tension are thought to mediate mechanosensation in many systems. Only one channel has been cloned that is unequivocably mechanically gated: the MscL channel in bacteria. Genetic screens for touch-insensitive nematodes or flies promise to identify the proteins that constitute a mechanosensory apparatus in eukaryotes. In Caenorhabditis elegans, the mec genes thus identified encode molecules for a candidate structure, which includes a “degenerin” channel tethered to specialized extracellular and intracellular structural proteins. In hair cells of the inner ear, evidence suggests that an extracellular tip link pulls on a channel, which attached intracellularly to actin via a tension-regulating myosin 1β. The channel and the tip link have not been cloned. Because degenerins and MscL homologs have not been found outside of nematodes and prokaryotes, respectively, and because intracellular and extracellular accessory structures apparently differ among organs and species, it may be that mechanosensory channel complexes evolved multiple times.
Evidence for the Defectiveness of the Harris Strain of Rous Sarcoma Virus
Authors: Richard H. Reamer, William Okazaki
Journal: JNCI Journal of the National Cancer Institute (1970)

A noncytopathic avian leukosis virus was isolated from the Harris strain of Rous sarcoma virus (HA-RSV) and was referred to as Rous-associated virus (RAV-6). From viral interference and neutralization tests, RAV-6 was found antigenically identical to HA-RSV. HA-RSV was classified previously as a subgroup B virus based on its host range. Four clones of transformed cells, whose supernatant fluid produced no neoplastic changes on chick embryo fibroblasts (CEF) susceptible to all known avian leukosis-sarcoma viruses (C/O), were derived from HA-RSV-infected C/O CEF by use of duck embryo fibroblasts as feeder layers. One of these clones was activated by all 8 strains of avian leukosis viruses tested, and the “activation potential” of the clone approached that of L-R cells derived from the Bryan high-titer strain of Rous sarcoma virus (BH-RSV). The other 3 clones had very low to no activating potential.
Preoperative Sensitivity and Specificity for Early-Stage Ovarian Cancer When Combining Cancer Antigen CA-125II, CA 15-3, CA 72-4, and Macrophage Colony-Stimulating Factor Using Mixtures of Multivariate Normal Distributions
Authors: Steven J. Skates, Nora Horick, Yinhua Yu, Feng-Ji Xu, Andrew Berchuck, Laura J. Havrilesky, Henk W.A. de Bruijn, Ate G.J. van der Zee, Robert P. Woolas, Ian J. Jacobs, Zhen Zhang, Robert C. Bast
Journal: Journal of Clinical Oncology (2004)

In CA-125-based ovarian cancer screening trials, overall specificity and screening sensitivity of ultrasound after an elevated CA-125 exceeded 99.6% and 70%, respectively, thereby yielding a positive predictive value (PPV) exceeding 10%. However, sensitivity for early-stage disease was only 40%. This study aims to increase preoperative sensitivity for early-stage ovarian cancer while maintaining the annual referral rate to ultrasound at 2% by combining information across CA-125II, CA 15-3, CA 72-4, and macrophage colony-stimulating factor (M-CSF). For direct comparisons between marker panels, all sensitivity results correspond to a 98% fixed first-line specificity (referral rate 2%).Logistic regression, classification tree, and mixture discriminant analysis (MDA) models were fit to a training data set of preoperative serum measurements (63 patients, 126 healthy controls) from one center. Estimates from the training set applied to an independent validation set (60 stage I to II patients, 98 healthy controls) from two other centers provided unbiased estimates of sensitivity.Preoperative sensitivities for early-stage disease of the optimal panels were 45% for CA-125II; 67% for CA-125II and CA 72-4; 70% for CA-125II, CA 72-4, and M-CSF; and 68% for all four markers (latter two results using MDA).Efficiently combining information on CA-125II, CA 72-4, and M-CSF significantly increased preoperative early-stage sensitivity from 45% with CA-125II alone to 70%, while maintaining 98% first-line specificity. Screening trials with these markers using MDA followed by referral to ultrasound may maintain previously high levels of specificity and PPV, while significantly increasing early-stage screening sensitivity. MDA is a useful, biologically justified method for combining biomarkers.
Increased levels of tissue plasminogen activator with a low plasminogen activator inhibitor‐1 in a patient with postoperative bleeding
Authors: Andrzej J. Stankiewicz, James P. Crowley, Manfred Steiner
Journal: American Journal of Hematology (1991)

Abstract Recurrent postoperative bleeding in a previously healthy man with a moderate prolongation of PT and PTT which did not correct with vigorous fresh‐frozen plasma infusion was identified as a unique abnormality of the fibrinolytic system: a combination of an excess of tissue plasminogen activator (t‐PA) at 300% of normal activity accompanied by a concurrent deficiency of plasminogen activator inhibitor‐1 activity (PAI‐1) of 10‐20% of normal activity. This observation underscores the potentially important regulatory role of PAI‐1 in the degree to which clinical manifestations of bleeding tendencies may occur in patients in whom an excess amount of t‐PA is expressed.
A patient's wish: anakinra in pregnancy
Authors: C T Berger, M Recher, U Steiner, T M Hauser
Journal: Annals of the Rheumatic Diseases (2009)

Patients with adult-onset Still’s disease (AOSD) are at increased risk for adverse outcomes of pregnancy. An increased rate of preterm birth, intrauterine growth retardation and a possible influence of disease activity on pregnancy outcome have been reported.1 Interleukin 1 (IL1) is thought to have a key role in the pathogenesis of AOSD. Interestingly, it has also been related to an increased risk of preterm birth in animal models.2 3 An increasing number of reports on treatment of refractory AOSD with IL1 receptor antagonist (anakinra) emphasise its dramatic therapeutic effect and the rarity of its adverse events.4 5 However, its effects in pregnancy are not well known. Here we report successful continuous treatment of AOSD during pregnancy and breastfeeding.

A 33-year-old woman with …
Phase I Trial of Toll-Like Receptor 9 Agonist PF-3512676 with and Following Rituximab in Patients with Recurrent Indolent and Aggressive Non–Hodgkin's Lymphoma
Authors: John P. Leonard, Brian K. Link, Christos Emmanouilides, Stephanie A. Gregory, Daniel Weisdorf, Jeffrey Andrey, John Hainsworth, Joseph A. Sparano, Donald E. Tsai, Sandra Horning, Arthur M. Krieg, George J. Weiner
Journal: Clinical Cancer Research (2007)

Abstract Purpose: PF-3512676 (formerly CpG 7909) is a novel Toll-like receptor 9–activating oligonucleotide with single-agent antitumor activity that augments preclinical rituximab efficacy. This Phase I trial was designed to investigate the safety, tolerability, and preliminary antitumor activity of PF-3512676 in combination with rituximab. Experimental Design: Patients with relapsed/refractory CD20+ B cell non–Hodgkin's lymphoma received i.v. rituximab (375 mg/m2/week for 4 weeks) and PF-3512676 weekly for 4 weeks either i.v. (0.04, 0.16, 0.32, or 0.48 mg/kg) or s.c. (0.01, 0.04, 0.08, or 0.16 mg/kg). An additional extended-treatment cohort received 4 weeks of 0.24 mg/kg s.c. PF-3512676 in combination with rituximab followed by s.c. PF-3512676 alone weekly for 20 weeks. Results: Patients (N = 50) had received a median of three prior therapies (range, 1-11) including rituximab in 80% of patients. Treatment-related adverse events occurred in 11 of 19 (58%) i.v. patients, 15 of 19 (79%) s.c. patients, and all 12 patients in the extended-treatment cohort. Most common adverse events were mild to moderate systemic flu-like symptoms and injection-site reactions (s.c. cohorts only). Grade 3/4 neutropenia occurred in four patients. Objective responses occurred in 12 of 50 (24%) patients overall and in 6 of 12 (50%) patients in the extended-treatment cohort, including 2 patients with rituximab-refractory disease. Conclusion: Brief or extended-duration PF-3512676 can be safely administered in combination with rituximab in patients with relapsed/refractory non–Hodgkin's lymphoma.
Long Term Protection Against New Sensitization After Milk-Epit In Mice Sensitized To Milk Is Mediated By Tregs
Authors: Pierre Henri Benhamou, Vincent Dioszeghy, Emilie Puteaux, Mélanie Ligouis, Véronique Dhelft, Camille Plaquet, Christophe Dupont, Lucie Mondoulet
Journal: Journal of Allergy and Clinical Immunology (2014)
Age-Dependent Prognostic Effects of Genetic Alterations in Glioblastoma
Authors: Tracy T. Batchelor, Rebecca A. Betensky, J. Matthew Esposito, Loc-Duyen D. Pham, Molly V. Dorfman, Nicole Piscatelli, Sarah Jhung, David Rhee, David N. Louis
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Although the genetic alterations in glioblastoma have been well characterized, reports regarding their prognostic effects have been inconsistent. Experimental Design: In this series of 140 consecutive cases of glioblastoma treated at a single center, we analyzed the frequency, age dependency and prognostic effects of TP53 mutation, CDKN2A/p16 deletion, EGFR amplification, as well as loss of chromosome 1p, chromosome 10q, and chromosome 19q. The complete set of genetic alterations was available on 60 of 140 patients. Results: In this cohort of glioblastoma cases, TP53 mutation was significantly associated with patient age. The prognostic effects of TP53 mutation, EGFR amplification, CDKN2A/p16 alterations, and loss of chromosome 1p were dependent on the age of the patient. Conclusions: This is the first observation that the prognostic effects of TP53, 1p, and CDKN2A/p16 alterations are dependent on patient age. These observations concerning the interactions of age and genetic changes in glioblastoma suggest that tumorigenic pathways to glioblastoma vary with the age of the patient and that future molecular marker studies should carefully evaluate the potential age-dependent prognostic effects of these biological variables. The inconsistent or negative prognostic effects of molecular markers reported in prior studies of glioblastoma may be because different effects at different ages may have resulted in a cancellation of an overall effect in the entire cohort.
Mechanism of Purinergic Activation of Endothelial Nitric Oxide Synthase in Endothelial Cells
Authors: Cleide Gonçalves da Silva, Anke Specht, Barbara Wegiel, Christiane Ferran, Elzbieta Kaczmarek
Journal: Circulation (2009)

Background— Decreased endothelial nitric oxide (NO) synthase (eNOS) activity and NO production are critical contributors to the endothelial dysfunction and vascular complications observed in many diseases, including diabetes mellitus. Extracellular nucleotides activate eNOS and increase NO generation; however, the mechanism of this observation is not fully clarified. Methods and Results— To elucidate the signaling pathway(s) leading to nucleotide-mediated eNOS phosphorylation at Ser-1177, human umbilical vein endothelial cells were treated with several nucleotides, including ATP, UTP, and ADP, in the presence or absence of selective inhibitors. These experiments identified P2Y1, P2Y2, and possibly P2Y4 as the purinergic receptors involved in eNOS phosphorylation and demonstrated that this process was adenosine independent. Nucleotide-induced eNOS phosphorylation and activity were inhibited by BAPTA-AM (an intracellular free calcium chelator), rottlerin (a protein kinase Cδ inhibitor), and protein kinase Cδ siRNA. In contrast, blockade of AMP-activated protein kinase, calcium/calmodulin-dependent kinase II, calcium/calmodulin-dependent kinase kinase, serine/threonine protein kinase B, protein kinase A, extracellular signal-regulated kinase 1/2, and p38 mitogen-activated protein kinase did not affect nucleotide-mediated eNOS phosphorylation. Conclusions— The present study indicates that extracellular nucleotide–mediated eNOS phosphorylation is calcium and protein kinase Cδ dependent. This newly identified signaling pathway opens new therapeutic avenues for the treatment of endothelial dysfunction.
Regulation of Arterial Thrombolysis by Plasminogen Activator Inhibitor-1 in Mice
Authors: Peter M. Farrehi, C. Keith Ozaki, Peter Carmeliet, William P. Fay
Journal: Circulation (1998)

Background —Platelet-rich arterial thrombi are resistant to lysis by plasminogen activators. However, the mechanisms underlying thrombolysis resistance are poorly defined. Plasminogen activator inhibitor-1 (PAI-1), which is present in plasma, platelets, and vascular endothelium, may be an important determinant of the resistance of arterial thrombi to lysis. However, in vitro studies examining the regulation of platelet-rich clot lysis by PAI-1 have yielded inconsistent results. Methods and Results —We developed a murine arterial injury model and applied it to wild-type ( PAI-1 +/+) and PAI-1–deficient ( PAI-1 −/−) animals. FeCl 3 was used to induce carotid artery thrombosis. Thrombi consisted predominantly of dense platelet aggregates, consistent with the histology of thrombi in large-animal arterial injury models and human acute coronary syndromes. To examine the role of PAI-1 in regulating endogenous clearance of platelet-rich arterial thrombi, thrombi were induced in 22 PAI-1 +/+ mice 14 PAI-1 −/− mice. Twenty-four hours later, the amount of residual thrombus was determined by histological analysis of multiple transverse sections of each artery. Residual thrombus was detected in 55 of 85 sections (64.7%) obtained from PAI-1 +/+ mice compared with 19 of 56 sections (33.9%) from PAI-1 −/− mice ( P =.009). Computer-assisted planimetry analysis revealed that mean thrombus cross-sectional area was 0.033±0.027 mm 2 in PAI-1 +/+ mice versus 0.016±0.015 mm 2 in PAI-1 −/− mice ( P =.048). Conclusions —PAI-1 is an important determinant of thrombolysis at sites of arterial injury. Application of this model to other genetically altered mice should prove useful for studying the molecular determinants of arterial thrombosis and thrombolysis.