tbuckley/cabot-search huggingface dataset:
Phase I and Pharmacokinetic Study of Topotecan Administered Orally Once Daily for 5 Days for 2 Consecutive Weeks to Pediatric Patients With Refractory Solid Tumors
Authors: Najat C. Daw, Victor M. Santana, Lisa C. Iacono, Wayne L. Furman, Dana R. Hawkins, Peter J. Houghton, J. Carl Panetta, Amar J. Gajjar, Clinton F. Stewart
Journal: Journal of Clinical Oncology (2004)

We conducted a phase I trial of the injectable formulation of topotecan given orally once daily for 5 days for 2 consecutive weeks (qd x 5 x 2) in pediatric patients with refractory solid tumors.Cohorts of two to six patients received oral topotecan at 0.8, 1.1, 1.4, 1.8, and 2.3 mg/m(2)/d every 28 days for a maximum of six courses. Twenty patients (median age, 10.6 years) received a total of 51 courses. Eight patients received topotecan capsules during course 2 only.Dose-limiting toxicity occurred at 2.3 mg/m(2)/d and consisted of prolonged grade 4 neutropenia (n = 2), grade 3 stomatitis as a result of radiation recall (n = 1), grade 3 hemorrhage (epistaxis) in the presence of grade 4 thrombocytopenia (n = 1), and grade 3 diarrhea in the presence of Clostridium difficile infection (n = 1). Dose-limiting, prolonged grade 4 neutropenia and thrombocytopenia occurred in one patient at 1.4 mg/m(2)/d. Infrequent toxicities were mild nausea, vomiting, elevated liver ALT or AST, and rash. The maximum-tolerated dosage was 1.8 mg/m(2)/d; the mean (+/- standard deviation) area under the plasma concentration-time curve for topotecan lactone at this dosage was 20.9 +/- 8.4 ng/mL. h. The population mean (+/- standard error) oral bioavailability of the injectable formulation was 0.27 +/- 0.03; that of capsules was 0.36 +/- 0.06 (P =.16). Disease stabilized in nine of 19 assessable patients for 1.5 to 6 months.Oral topotecan (1.8 mg/m(2)/d) on a qd x 5 x 2 schedule is well tolerated and warrants additional testing in pediatric patients.
Interleukin-6 Induces Monocyte Chemotactic Protein-1 in Peripheral Blood Mononuclear Cells and in the U937 Cell Line
Authors: Priscilla Biswas, Fanny Delfanti, Sergio Bernasconi, Manuela Mengozzi, Manuela Cota, Nadia Polentarutti, Alberto Mantovani, Adriano Lazzarin, Silvano Sozzani, Guido Poli
Journal: Blood (1998)
Translational Control in Synaptic Plasticity and Cognitive Dysfunction
Authors: Shelly A. Buffington, Wei Huang, Mauro Costa-Mattioli
Journal: Annual Review of Neuroscience (2014)

Activity-dependent changes in the strength of synaptic connections are fundamental to the formation and maintenance of memory. The mechanisms underlying persistent changes in synaptic strength in the hippocampus, specifically long-term potentiation and depression, depend on new protein synthesis. Such changes are thought to be orchestrated by engaging the signaling pathways that regulate mRNA translation in neurons. In this review, we discuss the key regulatory pathways that govern translational control in response to synaptic activity and the mRNA populations that are specifically targeted by these pathways. The critical contribution of regulatory control over new protein synthesis to proper cognitive function is underscored by human disorders associated with either silencing or mutation of genes encoding proteins that directly regulate translation. In light of these clinical implications, we also consider the therapeutic potential of targeting dysregulated translational control to treat cognitive disorders of synaptic dysfunction.
Endoplasmic Reticulum Stress in the Heart
Authors: Christopher C. Glembotski
Journal: Circulation Research (2007)

Over the last decade, it has become clear that the accumulation of misfolded proteins contributes to a number of neurodegenerative, immune, and endocrine pathologies, as well as other age-related illnesses. Recent interest has focused on the possibility that the accumulation of misfolded proteins can also contribute to vascular and cardiac diseases. In large part, the misfolding of proteins takes place during synthesis on free ribosomes in the cytoplasm or on endoplasmic reticulum ribosomes. In fact, even under optimal conditions, ≈30% of all newly synthesized proteins are rapidly degraded, most likely because of improper folding. Accordingly, stresses that perturb the folding of proteins during or soon after synthesis can lead to the accumulation of misfolded proteins and to potential cellular dysfunction and pathological consequences. To avert such outcomes, cells have developed elaborate protein quality-control systems for detecting misfolded proteins and making appropriate adjustments to the machinery responsible for protein synthesis and/or degradation. Important contributors to protein quality control include cytosolic and organelle-targeted molecular chaperones, which help fold and stabilize proteins from unfolding, and the ubiquitin proteasome system, which degrades terminally misfolded proteins. Both of these systems play important roles in cardiovascular biology. The focus of this review is the endoplasmic reticulum stress response, a protein quality-control and signal-transduction system that has not been well studied in the context of cardiovascular biology but that could be important for vascular and cardiac health and disease.
Smoking Cessation Guidelines for Health Professionals---A guide to effective smoking cessation interventions for the health care system
Authors: M. RAW, A. McNEILL, R. WEST
Journal: Thorax (1998)

The efficiency of strontium selenite and selenite F broths in the isolation of <i>S. typhi</i> from 625 clinical stool specimens were compared. A total of 126 strains of <i>S. typhi</i> were detected. Of these, 96 (76%) were isolated with selenite F broth and 118 (94%) were isolated with strontium selenite broth. At the same time, the number of false positive isolates accruing to strontium selenite broth was less than that accruing to selenite F broth. The superiority of strontium selenite broth over selenite F broth was more obvious when relatively few typhoid bacilli were present in faeces, eg, after antibiotic therapy, or when stools had been left for prolonged periods at room termperature. In the isolation of <i>S. typhi</i> with strontium selenite broth, salmonella-shigella agar was found to be a better plating medium than xylose lysine desoxycholate agar.
Heparin and heparinoids prevent the binding of immune complexes containing nucleosomal antigens to the GBM and delay nephritis in MRL/lpr mice
Authors: Mieke C.J. van Bruggen, Birgitte Walgreen, Truus P.M. Rijke, Marc J.A.M.M. Corsius, Karel J.M. Assmann, Ruud J.T. Smeenk, Gijs W.K. van Dedem, Kees Kramers, Jo H.M. Berden
Journal: Kidney International (1996)
Association between lichen sclerosus et atrophicus and primary biliary cirrhosis
Authors: R.H.Meyrick Thomas, C.M. Ridley, D.H. McGibbon, M.M. Black
Journal: British Journal of Dermatology (1986)

Journal Article Association between lichen sclerosus et atrophicus and primary biliary cirrhosis Get access R.H.Meyrick Thomas, R.H.Meyrick Thomas Departments of Dermatology, St Bartholomew's Hospital, Whittington Hospital and St Thomas' Hospital, London, U.K. Search for other works by this author on: Oxford Academic Google Scholar C.M. Ridley, C.M. Ridley Departments of Dermatology, St Bartholomew's Hospital, Whittington Hospital and St Thomas' Hospital, London, U.K. Search for other works by this author on: Oxford Academic Google Scholar D.H. McGibbon, D.H. McGibbon Departments of Dermatology, St Bartholomew's Hospital, Whittington Hospital and St Thomas' Hospital, London, U.K. Search for other works by this author on: Oxford Academic Google Scholar M.M. Black M.M. Black Departments of Dermatology, St Bartholomew's Hospital, Whittington Hospital and St Thomas' Hospital, London, U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 114, Issue 4, 1 April 1986, Pages 514–515, https://doi.org/10.1111/j.1365-2133.1986.tb02860.x Published: 01 April 1986
Overgeneralization of Conditioned Fear as a Pathogenic Marker of Panic Disorder
Authors: Shmuel Lissek, Stephanie Rabin, Randi E. Heller, David Lukenbaugh, Marilla Geraci, Daniel S. Pine, Christian Grillon
Journal: American Journal of Psychiatry (2009)

Classical conditioning features prominently in many etiological accounts of panic disorder. According to such accounts, neutral conditioned stimuli present during panic attacks acquire panicogenic properties. Conditioned stimuli triggering panic symptoms are not limited to the original conditioned stimuli but are thought to generalize to stimuli resembling those co-occurring with panic, resulting in the proliferation of panic cues. The authors conducted a laboratory-based assessment of this potential correlate of panic disorder by testing the degree to which panic patients and healthy subjects manifest generalization of conditioned fear.Nineteen patients with a DSM-IV-TR diagnosis of panic disorder and 19 healthy comparison subjects were recruited for the study. The fear-generalization paradigm consisted of 10 rings of graded size presented on a computer monitor; one extreme size was a conditioned danger cue, the other extreme a conditioned safety cue, and the eight rings of intermediary size created a continuum of similarity from one extreme to the other. Generalization was assessed by conditioned fear potentiating of the startle blink reflex as measured with electromyography (EMG).Panic patients displayed stronger conditioned generalization than comparison subjects, as reflected by startle EMG. Conditioned fear in panic patients generalized to rings with up to three units of dissimilarity to the conditioned danger cue, whereas generalization in comparison subjects was restricted to rings with only one unit of dissimilarity.The findings demonstrate a marked proclivity toward fear overgeneralization in panic disorder and provide a methodology for laboratory-based investigations of this central, yet understudied, conditioning correlate of panic. Given the putative molecular basis of fear conditioning, these results may have implications for novel treatments and prevention in panic disorder.
Expression of the Chemokine Receptor CXCR3 and Its Ligand IP-10 During Human Cardiac Allograft Rejection
Authors: Michael Melter, Andrea Exeni, Marlies E.J. Reinders, James C. Fang, Gearoid McMahon, Peter Ganz, Wayne W. Hancock, David M. Briscoe
Journal: Circulation (2001)

Background Chemokines play an essential role in regulating the infiltration of leukocytes into allografts in experimental models. Little is known of their expression or function after human cardiac transplantation. Methods and Results We analyzed 169 sequential human endomyocardial biopsies by immunocytochemistry for infiltration by CD3 + T cells and the expression of the chemokine receptors CCR1, CCR3, CCR5, and CXCR3. In both cross-sectional and longitudinal analyses, the expression of each of the chemokine receptors correlated with the degree of CD3 + T-cell infiltration. In particular, the expression of CXCR3 was temporally and spatially associated with CD3 + T-cell infiltrates and correlated with the histopathological diagnosis of acute rejection (OR, 11.73 and 4.05, respectively; P &lt;0.001). Of 7 patients followed up longitudinally for 1 year, 4 with consecutive biopsies developed intimal thickening by intravascular ultrasound. In these patients, there was a trend for persistent expression of CD3- and CXCR3-expressing infiltrates in the later part of the first posttransplant year. The chemokines eotaxin, IP-10, lymphotactin, MCP-1, Mig, RANTES, and SDF-1 were examined in an additional 35 biopsies by RT-PCR. Eotaxin, lymphotactin, MCP-1, Mig, and SDF-1 were present in both normal and rejecting biopsies. However, the CXCR3 ligand IP-10, which was rarely expressed in normal biopsies, was markedly induced in acute rejection (OR, 19.43; P =0.01). Conclusions The presence of CXCR3 + T cells and the CXCR3 ligand IP-10 within endomyocardial biopsies is strongly associated with acute rejection. The CXCR3–IP-10 interaction warrants consideration as a therapeutic target in the management of cardiac allograft recipients.
Language, tools and brain: The ontogeny and phylogeny of hierarchically organized sequential behavior
Authors: Patricia M. Greenfield
Journal: Behavioral and Brain Sciences (1991)

Abstract During the first two years of human life a common neural substrate (roughly Broca's area) underlies the hierarchical organization of elements in the development of speech as well as the capacity to combine objects manually, including tool use. Subsequent cortical differentiation, beginning at age two, creates distinct, relatively modularized capacities for linguistic grammar and more complex combination of objects. An evolutionary homologue of the neural substrate for language production and manual action is hypothesized to have provided a foundation for the evolution of language before the divergence of the hominids and the great apes. Support comes from the discovery of a Broca's area homologue and related neural circuits in contemporary primates. In addition, chimpanzees have an identical constraint on hierarchical complexity in both tool use and symbol combination. Their performance matches that of the two-year-old child who has not yet developed the neural circuits for complex grammar and complex manual combination of objects.
FDG-PET in diagnostic work-up of pulmonary artery sarcomas
Authors: C. Tueller, R. Fischer Biner, S. Minder, M. Gugger, C. Stoupis, T. M. Krause, T. P. Carrel, R. A. Schmid, P. Vock, L. P. Nicod
Journal: European Respiratory Journal (2010)

FDG-PET in diagnostic work-up of pulmonary artery sarcomas
Endpoints and clinical trial design for nonalcoholic steatohepatitis
Authors: Arun J. Sanyal, Elizabeth M. Brunt, David E. Kleiner, Kris V. Kowdley, Naga Chalasani, Joel E. Lavine, Vlad Ratziu, Arthur McCullough
Journal: Hepatology (2011)

Abstract: Nonalcoholic fatty liver disease is a common cause of chronic liver disease in the general population. Nonalcoholic steatohepatitis (NASH), the aggressive form of nonalcoholic fatty liver disease, is associated with an increased risk of liver-related mortality and cardiovascular disease. At present, a liver biopsy is the only generally acceptable method for the diagnosis of NASH and assessment of its progression toward cirrhosis. Although several treatments have shown evidence of efficacy in clinical trials of varying design, there are no approved treatments for NASH, and published trials are often too divergent to allow meaningful comparisons. There is thus a lack of established noninvasive, point-of-care diagnostics and approved treatment on one hand and a substantial population burden of disease on the other. These provide the rationale for developing consensus on key endpoints and clinical trial design for NASH. Conclusion: This article summarizes the consensus arrived at a meeting of the American Association for the Study of Liver Diseases on the key endpoints and specific trial design issues that are germane for development of diagnostic biomarkers and treatment trials for NASH. (HEPATOLOGY 2011;)
Oral tolerance protocols improve the rate of recovery of cow milk and egg allergies: Randomized study in 60 children with cow's milk allergy and 90 children with egg allergy
Authors: M. Morisset, D. Moneret-Vautrin, L. Guénard, J. Cuny, P. Frentz, R. Hatahet, C. Hanss, E. Beaudouin, N. Petit, S. Frémont, G. Kanny
Journal: Journal of Allergy and Clinical Immunology (2005)
Multidrug Resistance Protein 4 Protects Bone Marrow, Thymus, Spleen, and Intestine from Nucleotide Analogue–Induced Damage
Authors: Martin G. Belinsky, Ping Guo, Kun Lee, Feng Zhou, Elena Kotova, Alex Grinberg, Heiner Westphal, Irina Shchaveleva, Andres Klein-Szanto, James M. Gallo, Gary D. Kruh
Journal: Cancer Research (2007)

Abstract Nucleoside-based analogues are mainstays in the treatment of cancer, viral infections, and inflammatory diseases. Recent studies showing that the ATP-binding cassette transporter, multidrug resistance protein 4, is able to efflux nucleoside and nucleotide analogues from transfected cells suggests that the pump may affect the efficacy of this class of agents. However, the in vivo pharmacologic functions of the pump are largely unexplored. Here, using Mrp4−/− mice as a model system, and the nucleotide analogue, 9′-(2′-phosphonylmethoxyethyl)-adenine (PMEA) as a probe, we investigate the ability of Mrp4 to function in vivo as an endogenous resistance factor. In the absence of alterations in plasma PMEA levels, Mrp4-null mice treated with PMEA exhibit increased lethality associated with marked toxicity in several tissues. Affected tissues include the bone marrow, spleen, thymus, and gastrointestinal tract. In addition, PMEA penetration into the brain is increased in Mrp4−/− mice. These findings indicate that Mrp4 is an endogenous resistance factor, and that the pump may be a component of the blood-brain barrier for nucleoside-based analogues. This is the first demonstration that an ATP-binding cassette transporter can affect in vivo tissue sensitivity towards this class of agents. [Cancer Res 2007;67(1):262–8]
Phenotypic and functional analyses show stem cell-derived hepatocyte-like cells better mimic fetal rather than adult hepatocytes
Authors: Melissa Baxter, Sarah Withey, Sean Harrison, Charis-Patricia Segeritz, Fang Zhang, Rebecca Atkinson-Dell, Cliff Rowe, Dave T. Gerrard, Rowena Sison-Young, Roz Jenkins, Joanne Henry, Andrew A. Berry, Lisa Mohamet, Marie Best, Stephen W. Fenwick, Hassan Malik, Neil R. Kitteringham, Chris E. Goldring, Karen Piper Hanley, Ludovic Vallier, Neil A. Hanley
Journal: Journal of Hepatology (2014)

Hepatocyte-like cells (HLCs), differentiated from pluripotent stem cells by the use of soluble factors, can model human liver function and toxicity. However, at present HLC maturity and whether any deficit represents a true fetal state or aberrant differentiation is unclear and compounded by comparison to potentially deteriorated adult hepatocytes. Therefore, we generated HLCs from multiple lineages, using two different protocols, for direct comparison with fresh fetal and adult hepatocytes.
Activation of Epithelial Growth Factor Receptor Pathway by Unsaturated Fatty Acids
Authors: Nathalie Vacaresse, Isabelle Lajoie-Mazenc, Nathalie Augé, Isabelle Suc, Marie-Françoise Frisach, Robert Salvayre, Anne Nègre-Salvayre
Journal: Circulation Research (1999)

Abstract —Nonesterified fatty acids (NEFAs) are acutely liberated during lipolysis and are chronically elevated in pathological conditions, such as insulin resistance, hypertension, and obesity, which are known risk factors for atherosclerosis. The purpose of this study was to investigate the effect and mechanism of action of NEFAs on the epithelial growth factor (EGF) receptor (EGFR). In the ECV-304 endothelial cell line, unsaturated fatty acids triggered a time- and dose-dependent tyrosine phosphorylation of EGFR (polyunsaturated fatty acids [PUFAs] were the most active), whereas saturated FAs were inactive. Although less potent than PUFAs, oleic acid (OA) was used because it is prominent in the South European diet and is only slightly oxidizable (thus excluding oxidation derivatives). EGFR is activated by OA independent of any autocrine secretion of EGF or other related mediators. OA-induced EGFR autophosphorylation triggered EGFR signaling pathway activation (as assessed through coimmunoprecipitation of SH2 proteins such as SHC, GRB2, and SHP-2) and subsequent p42/p44 mitogen-activated protein kinase (as shown by the use of EGFR- deficient B82L and EGFR- transduced B82LK + cell lines). OA induced in vitro both autophosphorylation and activation of intrinsic tyrosine kinase of immunopurified EGFR, thus suggesting that EGFR is a primary target of OA. EGFR was also activated by mild surfactants, Tween-20 and Triton X-100, both in vitro (on immunopurified EGFR) and in intact living cells, thus indicating that EGFR is sensitive to amphiphilic molecules. These data suggest that EGFR is activated by OA and PUFAs, acts as a sensor for unsaturated fatty acids (and amphiphilic molecules), and is a potential transducer by which diet composition may influence vascular wall biology.
Spiritt (Study 20060141): a Randomized Phase 2 Study of 2nd-Line Treatment with Folfiri + Panitumumab or Bevacizumab for Wild-Type KRAS MCRC
Authors: Bilal Piperdi, Allen Cohn, J. Hecht, Shaker Dakhil, Mansoor Saleh, Mika Cline-Burkhardt, Ying Tian, William Go
Journal: Annals of Oncology (2013)
Long‐term effect of antiviral therapy on disease course after decompensation in patients with hepatitis B virus–related cirrhosis
Authors: Jeong Won Jang, Jong Young Choi, Young Seok Kim, Hyun Young Woo, Sung Kyu Choi, Chang Hyeong Lee, Tae Yeob Kim, Joo Hyun Sohn, Won Young Tak, Kwang‐Hyub Han
Journal: Hepatology (2015)

The effect of viral suppression on long-term disease outcome after decompensation in patients with hepatitis B virus (HBV)-related cirrhosis has not been established. The aim of this study was to determine the long-term effect of antiviral therapy (AVT) in patients with HBV-related decompensated cirrhosis. This was a multicenter, prospective, inception cohort study of 707 patients who presented with first-onset decompensated complications, including 284 untreated and 423 antiviral-treated patients (58 previously treated, 253 with early treatment, and 112 with delayed treatment). The primary endpoint was 5-year liver transplantation (LT)-free survival. Secondary endpoints included virological response (VR) and serological response and improvement in liver function. Despite baseline high HBV activity and worse liver function, antiviral-treated patients had significantly better transplant-free survival than untreated patients (5-year survival rates of 59.7% vs. 46.0%, respectively), with more apparent benefits from antivirals in Child-Turcotte-Pugh class B/C and high-viremia groups. The rate of VR and hepatitis B e antigen seroconversion at 5 years in antiviral-treated patients was 14.2% and 49.1%, respectively. A significant improvement in liver function was observed in treated versus untreated patients, with 33.9% of treated patients delisted for LT. Patients with early treatment had better clinical outcomes than those with delayed treatment. Survival was dependent on antiviral response, being significantly better in responders than in nonresponders or untreated cases. The initial benefit of AVT was negated over time in nonresponders. Antiviral treatment and maintained VR remained independently predictive of survival. The study results were corroborated by propensity score-matching analysis.AVT significantly modifies the natural history of decompensated cirrhosis, improving liver function and increasing survival. The results underscore the importance of promptly administering potent antiviral drugs to patients under consideration for LT.