tbuckley/cabot-search huggingface dataset:
Phase I and Pharmacodynamic Study of the Oral MEK Inhibitor CI-1040 in Patients With Advanced Malignancies
Authors: Patricia M. LoRusso, Alex A. Adjei, Mary Varterasian, Shirish Gadgeel, Joel Reid, David Y. Mitchell, Lorelei Hanson, Pamela DeLuca, Laura Bruzek, Jill Piens, Peggy Asbury, Keri Van Becelaere, Roman Herrera, Judith Sebolt-Leopold, Mark B. Meyer
Journal: Journal of Clinical Oncology (2005)

This phase I study was undertaken to define the toxicity, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD), and clinical activity of CI-1040, a small-molecule inhibitor of the dual-specificity kinases MEK(mitogen-activated protein kinase kinase) -1 and MEK2 , in patients with advanced malignancy.CI-1040 was tested in multiple daily dosing frequencies administered for 21 days repeated every 28 days leading ultimately to continuous administration, and effect of food on absorption was tested. Single dose and steady-state pharmacokinetics were assessed during cycle 1 and phosphorylated extracellular receptor kinase (pERK) levels were assessed in WBCs and also in tumor tissue from selected patients.Seventy-seven patients received CI-1040 at dose levels ranging from 100 mg QD to 800 mg tid. Grade 3 asthenia was dose limiting at the highest dose level tested, 800 mg tid administered with food. Ninety-eight percent of all drug-related adverse events were grade 1 or 2 in severity; most common toxicities included diarrhea, asthenia, rash, nausea, and vomiting. Plasma concentrations of CI-1040 and its active metabolite, PD 0184264, increased in a less than dose proportional manner from 100 to 800 mg QD. Administration with a high-fat meal resulted in an increase in drug exposure. The MTD and recommended phase II dose was 800 mg BID administered with food. Sixty-six patients were assessable for response. One partial response was achieved in a patient with pancreatic cancer and 19 patients (28%) achieved stable disease lasting a median of 5.5 months (range, 4 to 17 months). Inhibition of tumor pERK (median, 73%; range, 46% to 100%) was demonstrated in 10 patients.CI-1040 was well tolerated at 800 mg BID administered with food. Both target suppression and antitumor activity were demonstrated in this phase I study.
Does photodamage matter?
Authors: R. Marks
Journal: British Journal of Dermatology (1992)

Journal Article Does photodamage matter? Get access R. Marks R. Marks Department of Dermatology University of Wales College of Medicine Health Park, Cardiff, UK Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 127, Issue S41, 1 September 1992, Page 1, https://doi.org/10.1111/j.1365-2133.1992.tb16979.x Published: 01 September 1992
Familial Juvenile Hyperuricemic Nephropathy and Autosomal Dominant Medullary Cystic Kidney Disease Type 2
Authors: KARIN DAHAN, ARNO FUCHSHUBER, STAVROULA ADAMIS, MICHÈLE SMAERS, SABINE KROISS, GUY LOUTE, JEAN-PIERRE COSYNS, FRIEDHELM HILDEBRANDT, CHRISTINE VERELLEN-DUMOULIN, YVES PIRSON
Journal: Journal of the American Society of Nephrology (2001)

Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal dominant disorder heralded by hyperuricemia during childhood; it is characterized by chronic interstitial nephritis, with marked thickening of tubular basement membranes, and leads to progressive renal failure during adulthood. A gene for FJHN in two Czech families was recently mapped to chromosome 16p11.2, close to the MCKD2 locus, which is responsible for a variant of autosomal dominant medullary cystic kidney disease observed in an Italian family. In a large Belgian family with FJHN, a tight linkage between the disorder and the marker D16S3060, located within the MCKD2 locus on chromosome 16p12 (maximal two-point logarithmic odds score of 3.74 at a recombination fraction of θ = 0), was observed in this study. The candidate region was further narrowed to a 1.3-Mb interval between D16S501 and D16S3036. Together with the striking clinical and pathologic resemblance between previously reported medullary cystic kidney disease type 2 and FJHN occurring in the Belgian family (including the presence of medullary cysts), this study suggests that these two disorders are facets of the same disease.
Anti-Flt1 Peptide, a Vascular Endothelial Growth Factor Receptor 1–Specific Hexapeptide, Inhibits Tumor Growth and Metastasis
Authors: Dong-Goo Bae, Tae-Dong Kim, Ge Li, Wan-Hee Yoon, Chi-Bom Chae
Journal: Clinical Cancer Research (2005)

The purpose of this study was to develop antagonists specific for the vascular endothelial growth factor receptor 1 (VEGFR1) and to investigate the effects of the antagonists on the VEGF-induced endothelial cell functions and tumor progression.Hexapeptides that inhibit binding of VEGFR1 and VEGF were identified through screening of synthetic peptide library. A selected peptide, anti-Flt1, was investigated for binding specificity with various receptors and ligand peptides. Effects of the peptide on proliferation, cell migration, and fibrin gel-based angiogenesis of endothelial cells were also investigated. The activity of anti-Flt1, in vivo, was evaluated for inhibition of tumor growth and metastasis in VEGF-secreting cancer cell-implanted mice by s.c. injections of the peptide.Here, we report on a short peptide that binds to VEGFR1 and prevents binding of VEGF. A hexapeptide, anti-Flt1 (Gly-Asn-Gln-Trp-Phe-Ile or GNQWFI), was identified from peptide libraries. The anti-Flt1 peptide shows specificity toward binding to VEGFR1 and it inhibits binding of VEGF, placental growth factor (PlGF), and VEGF/PlGF heterodimer to VEGFR1. This peptide does not inhibit the proliferation of endothelial cells induced by VEGF and VEGF/PlGF heterodimer but it effectively blocks VEGF-induced migration of endothelial cells and their capacity to form capillary-like structures on fibrin gel-based in vitro angiogenesis system. Furthermore, growth and metastasis of VEGF-secreting tumor cells were also significantly inhibited by s.c. injections of anti-Flt1 peptide in nude mice. Accordingly, VEGF-induced migration and capillary formation are mediated through VEGFR1, and these processes may play an important role in the growth and metastasis of VEGF-secreting tumors.We show that a peptide (anti-Flt1) specific for VEGFR1 inhibits growth and metastasis of tumor that secretes VEGF. The effects on endothelial cell functions, in vitro, indicate that the anticancer activity of anti-Flt1 peptide with reduced blood vessel density could also be due to the blocking of VEGFR1-mediated endothelial cell migration and tube formation. Although the effects of anti-Flt1 peptide still remain to be further characterized, the receptor 1-specific peptide antagonist, anti-Flt1, has potential as a therapeutic agent for various angiogenesis-related diseases, especially cancer.
Protection against lethal toxic shock by targeted disruption of the CD28 gene.
Authors: B Saha, D M Harlan, K P Lee, C H June, R Abe
Journal: The Journal of Experimental Medicine (1996)

Toxic shock syndrome (TSS) is a multi system disorder resulting from superantigen-mediated cytokine production. Nearly 90% of the clinical cases of TSS arise due to an exotoxin, toxic shock syndrome toxin-1 (TSST-1), elaborated by toxigenic strains of Staphylococcus aureus. It is clearly established that besides antigen-specific signals a variety of costimulatory signals are required for full T cell activation. However, the nature and potential redundancy of costimulatory signals are incompletely understood, particularly with regards to superantigen-mediated T cell activation in vivo. Here we report that CD28-deficient mice (CD28-/-) are completely resistant to TSST-1-induced lethal TSS while CD28 (+/-) littermate mice were partially resistant to TSST-1. The mechanism for the resistance of the CD28 (-/-) mice was a complete abrogation of TNF-alpha accumulation in the serum and a nearly complete (90%) impairment of IFN-gamma secretion in response to TSST-1 injection. In contrast, the serum level of IL-2 was only moderately influenced by the variation of CD28 expression. CD28 (-/-) mice retained sensitivity to TNF-alpha as demonstrated by equivalent lethality after cytokine injection. These findings establish an essential requirement for CD28 costimulatory signals in TSST-1-induced TSS. The hierarchy of TSST-1 resistance among CD28 wild-type (CD28+/+), CD28 heterozygous (CD28+/-), and CD28-/- mice suggests a gene-dose effect, implying that the levels of T cell surface CD28 expression critically regulate superantigen-mediated costimulation. Finally, as these results demonstrate the primary and non-redundant role of CD28 receptors in the initiation of the in vivo cytokine cascade, they suggest therapeutic approaches for superantigen-mediated immunopathology.
Outlook for Acute Lymphocytic Leukemia in Children in 1982
Authors: J V Simone
Journal: Annual Review of Medicine (1981)

The treatment of childhood ALL has been remarkedly successful over the past 30 years of the chemotherapy era. A substantial proportion of patients, perhaps 40--50%, are apparently cured with currently available therapy. However, optimal therapy has not yet been devised because of substantial therapeutic failures in the form of relapse and unacceptable side-effects. Remission induction therapy is the most settled aspect of therapy. The addition of asparaginase or an anthracycline to prednisone and vincristine is highly effective. Preventive central nervous system therapy is under revision and study. It is likely that a variety of approaches will be equally effective. Continuation (maintenance) therapy is in the most need of revision because of a majority of therapeutic failures are due to bone marrow relapse--the failure of systemic therapy to prevent emergence of resistant leukemia cells. The optimal duration of therapy has not been established, the relapse rate after cessation of therapy lasting 2-3 years currently being 20-25%. Bone marrow transplantation during remission shows promise as a therapeutic modality, particularly if autologous techniques are successful. The most promising development, however, is our increasing understanding of biological subpopulations of leukemia cells. This ultimately may help us develop more effective and specific therapy for childhood ALL.
Anatomy of the Ventricular Coronary Arteries in the Dog
Authors: EMIL BLAIR
Journal: Circulation Research (1961)

The ventricular coronary arterial system of the dog displays preponderance of the left in 100 per cent of the animals studied. The single most important source of blood supply is the left circumflex artery, which supplies not only most of the left ventricle, but also significant portions of the right ventricle. Details of the septal branch are described. Morphological implications concerning death or survival in experimental coronary occlusive procedures are discussed. A simple nomenclature is offered.
The Treatment Initiation Program: An Intervention to Improve Depression Outcomes in Older Adults
Authors: Jo Anne Sirey, Martha L Bruce, George S Alexopoulos
Journal: American Journal of Psychiatry (2004)

This pilot study tests the usefulness of the Treatment Initiation Program (TIP) to improve depression in older adults. The TIP is an individualized, early intervention to address older adults' attitudes (e.g., perceived need for care and stigma) about depression and treatment.Older adults with major depression seeking mental health treatment were randomly assigned to either pharmacotherapy alone or with the TIP. Severity was assessed with the Hamilton Depression Rating Scale at admission and at 6, 12, and 24 weeks. Mixed-effects models were calculated to evaluate the effects of the TIP.In mixed-effects models, TIP patients had a greater decrease in depression severity and reported less hopelessness than the patients receiving usual care. TIP patients were more likely to remain in treatment 12 and 24 weeks after seeking care.These data support the usefulness of the TIP to improve depression outcomes and treatment participation among older adults.
Restriction of Late Cerebral Cortical Progenitors to an Upper-Layer Fate
Authors: Gretchen D Frantz, Susan K McConnell
Journal: Neuron (1996)

Early in development, neural progenitors in cerebral cortex normally produce neurons of several layers during successive cell divisions. The laminar fate of their daughters depends on environmental cues encountered just before mitosis. At the close of neurogenesis, however, cortical progenitors normally produce neurons destined only for the upper layers. To assess the developmental potential of these cells, upper-layer progenitors were transplanted into the cerebral cortex of younger hosts, in which deep-layer neurons were being generated. These studies reveal that late cortical progenitors are not competent to generate deep-layer neurons and are instead restricted to producing the upper layers.
Trends in Children’s Exposure to Violence, 2003 to 2011
Authors: David Finkelhor, Anne Shattuck, Heather A. Turner, Sherry L. Hamby
Journal: JAMA Pediatrics (2014)

<h3>Importance</h3> The study suggests that years of public policy designed to reduce the burden of violence and victimization among youths is having some success. <h3>Objective</h3> To identify trends in children's exposure to violence, crime, and abuse from 2003 through 2011. <h3>Design, Setting, and Participants</h3> Three national telephone surveys of representative samples of children and caregivers from 2003, 2008, and 2011 were compared, all obtained using the Juvenile Victimization Questionnaire; samples included parents of children 2 to 9 years old and youth 10 to 17 years old. <h3>Exposures</h3> Direct and indirect experiences of violence, abuse, and victimization during the previous year. <h3>Main Outcomes and Measures</h3> Change in rates between 2003 and 2011 and between 2008 and 2011. <h3>Results</h3> Of 50 trends in exposure examined, there were 27 significant declines and no significant increases between 2003 and 2011. Declines were particularly large for assault victimization, bullying, and sexual victimization. There were also significant declines in the perpetration of violence and property crime. For the recession period between 2008 and 2011, there were 11 significant declines and no increases for 50 specific trends examined. Dating violence declined, as did one form of sexual victimization and some forms of indirect exposure. <h3>Conclusions and Relevance</h3> Victimization surveys with general population samples confirm patterns seen in police data and adult surveys. Crime and violence have been declining in the child and youth population as well.
Reactivity in Neoplasia, Preneoplasia, and Pregnancy of Lymphocytes Against Fetal Extracts: Cross-Reactions Between Man and Mouse&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: G Pasternak, B Schlott, J Reinhöfer, G Gryschek, B von Broen, S Albrecht
Journal: JNCI Journal of the National Cancer Institute (1982)

KCI extracts (3 M) from human fetuses were tested by macrophage electrophoretic mobility (MEMB), leukocyte migration inhibition, and/or leukocyte adherence inhibition techniques against lymphocytes-leukocytes from tumor-bearing humans and control persons. A positive MEMB test was found in 209 of 284 (73%) patients with various types of clinically manifest tumors. Only 15 of 134 (11 %) controls gave a positive reaction by the MEMB test. Leukocyte migration was significantly inhibited in 48 of 64 (75%) tumor patients, and leukocyte adherence was significantly inhibited in 40 of 50 (80%) tumor patients versus 7 of 50 (14%) and 10 of 54 (19%) in the corresponding controls. Lymphocyte reactivity to fetal extracts is also detectable in inbred XVII/Bin, CBA/Bln, and C3H/Bln mice bearing spontaneous or transplanted tumors of different etiology. Human and mouse fetal extracts gave cross-reactions. Lymphocytes from tumorbearing mice were reactive against fetal extracts from the cow, pig, sheep, guinea pig, cat, and chicken. Mice bearing benign skin warts induced by 7, 12-dimethylbenz[a]anthracene (DMBA) as well as DMBAtreated mice without visible skin lesions gave a positive MEMB test. Likewise, pregnancy is associated with lymphocyte reactivity to fetal extracts.
Strain Dependent Differences in Magnitude and Timing of Innate Immune Responses to Respiratory Syncytial Virus (RSV) in Human Monocyte Derived Dendritic Cells (MDDC)
Authors: P. Hillyer, A. Chen, M. Navarro, L.M. Schramm, V.P. Mane, D.M. Gold, N. Raviv, R.L. Rabin
Journal: Journal of Allergy and Clinical Immunology (2011)
Chromatin Topology and the Regulation of Antigen Receptor Assembly
Authors: Claudia Bossen, Robert Mansson, Cornelis Murre
Journal: Annual Review of Immunology (2012)

During an organism's ontogeny and in the adult, each B and T lymphocyte generates a unique antigen receptor, thereby creating the organism's ability to respond to a vast number of different antigens. The antigen receptor loci are organized into distinct regions that contain multiple variable (V), diversity (D), and/or joining (J) and constant (C) coding elements that are scattered across large genomic regions. In this review, we discuss the epigenetic modifications that take place in the different antigen receptor loci, the chromatin structure adopted by the antigen receptor loci to allow recombination of elements separated by large genomic distances, and the relationship between epigenetics and chromatin structure and how they relate to the generation of antigen receptor diversity.
The Community Mental Health Center in the Rural Area: Is the Present Model Appropriate?
Authors: DAVID N. DANIELS
Journal: American Journal of Psychiatry (1967)

The community mental health center model with its varied direct clinical services becomes a white elephant when applied to rural states and areas. The model does not fulfill the mental health needs of the people—of meeting them where they live and serving them through the utilization of available personnel and resources. An alternative, indirect services model, which emphasizes consultation, education, preventive psychiatry, and community psychiatry as community organization, is proposed and explored.
Changes in the Pulmonary Circulation after Bronchial Occlusion in Anesthetized Dogs and Cats
Authors: Gwenda R. Barer, Peter Howard, Janice R. McCurrie, John W. Shaw
Journal: Circulation Research (1969)

The effects of bronchial occlusion on the pulmonary circulation were studied in anesthetized cats and dogs. Immediately after occlusion, blood flow fell rapidly at normal pulmonary arterial pressure (–71% cats, –54% dogs), and in constant flow perfusion experiments, perfusion pressure rose (+50% cats, +28% dogs). These resistance changes were reversed by vasodilator drugs, alkali, or perfusion of the lung with arterial blood. We concluded that an active mechanism, probably an increase in vasomotor tone, was involved; a mechanical process would not be reversed in this way. Pulmonary venous Po 2 was the factor most closely related to the increase in resistance. In collapsing "oxygen-filled" lobes, compared with "air-filled" lobes the resistance change was delayed until the pulmonary venous Po 2 fell. Hypoventilation and ventilation with hypoxic mixtures causing a fall in pulmonary venous Po 2 similar to that due to collapse caused equivalent changes in blood flow. Changes in pH, Pco 2 and lung volume played a relatively minor role in resistance changes following collapse. The increase in resistance may be caused by a mechanism regulating ventilation-perfusion ratios in both normal and diseased lung.
The impact of a repeated bout of eccentric exercise on muscular strength, muscle soreness and creatine kinase.
Authors: L L Smith, M G Fulmer, D Holbert, M R McCammon, J A Houmard, D D Frazer, E Nsien, R G Israel
Journal: British Journal of Sports Medicine (1994)

The purpose of this study was to determine if there were any beneficial or detrimental effects regarding delayed onset muscle soreness (DOMS), serum creatine kinase (CK), and maximum concentric strength at 80% of 1-RMconc, if a bout of eccentric exercise was repeated at 48 h after an initial bout. A secondary purpose was to determine whether unaccustomed eccentrics might affect plasma cholesterol (TC). Twenty-six men were randomly assigned to a control (Group 1) or experimental group (Group 2). Both groups performed three sets (12 repetitions per set) of the eccentric phase of a chest press, at 80% of one repetition maximum (1-RMconc); Group 2 repeated this exercise 48 h later. DOMS and CK were measured before, and every 24 h for 8 days after; TC was measured before, and every 24 h for 4 days. Maximum strength during the concentric phase of a chest press (1-RMconc) was measured before and at 48-h intervals after. A repeated measures analysis of variance revealed a significant time effect (P &lt; 0.05) for DOMS, CK and strength, but no significant difference between groups (P &lt; 0.05). An interesting finding was the significant (P &lt; 0.05) reduction in TC at 24, 48 and 72 h, after exercise in both groups, which we hypothesized was associated with cellular repair. From these results we concluded that when a bout of eccentrics is repeated 48 h after an initial bout, there is no change in the characteristic time-course and/or intensity of DOMS, CK or 1-RMconc.
Netrin-1 Dampens Pulmonary Inflammation during Acute Lung Injury
Authors: Valbona Mirakaj, Cyril A Thix, Stefanie Laucher, Carina Mielke, Julio C Morote-Garcia, Marthe A Schmit, Janek Henes, Klaus E Unertl, David Köhler, Peter Rosenberger
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Rationale: Acute lung injury (ALI) is an inflammatory disorder characterized by hypoxemia and diffuse infiltration of neutrophils into the alveolar space. The migration and extravasation of neutrophils is guided through positive guidance cues, such as chemokines. Recent work has identified the neuronal guidance protein netrin-1 to be a negative guidance cue for leukocyte migration and to hold antiinflammatory potential.Objectives: To test the role of pulmonary netrin-1 during ALI.Methods: Pulmonary netrin-1 expression was evaluated during acute inflammation in vitro and in vivo; the netrin-1 promoter was studied using pGL4 luciferase reporter. ALI was induced through LPS inhalation and mechanical ventilation in wild-type, Ntn1+/−, and A2BAR−/− animals. Exogenous netrin-1 was used to evaluate its impact on pulmonary inflammation.Measurements and Main Results: Wild-type animals demonstrated repression of pulmonary netrin-1 after LPS inhalation. In vitro studies confirmed the repression of netrin-1. Studies in the putative netrin-1 promoter identified a nuclear factor-κB–dependent mechanism to be involved in this repression. Ntn1+/− animals demonstrated increased inflammatory changes after LPS inhalation compared with Ntn1+/+ animals. Reconstitution with netrin-1 dampened the infiltration of neutrophils and cytokine production in the alveolar space. This effect was dependent on the adenosine 2b receptor. The importance of netrin-1 for the control of pulmonary inflammation could be corroborated in a model of ventilator-induced lung injury.Conclusions: Pulmonary netrin-1 levels are repressed during ALI. This results in pronounced pulmonary damage, an increased infiltration of neutrophils, and increased pulmonary inflammation. Exogenous netrin-1 significantly dampens the extent of ALI through the adenosine 2B receptor.
Recombinant human angiostatin (rhAngiostatin) in combination with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer: a phase II study from Indiana University
Authors: A. Kurup, C.-W. Lin, D.J. Murry, L. Dobrolecki, D. Estes, C.T. Yiannoutsos, L. Mariano, C. Sidor, R. Hickey, N. Hanna
Journal: Annals of Oncology (2005)