tbuckley/cabot-search huggingface dataset:
Pharmacokinetics and Pharmacodynamics of Oral Etoposide in Children With Relapsed or Refractory Acute Lymphoblastic Leukemia
Authors: Mathew J. Edick, Amar Gajjar, Hazem H. Mahmoud, Matthijs E.C. van de Poll, Patricia L. Harrison, John C. Panetta, Gaston K. Rivera, Raul C. Ribeiro, John T. Sandlund, James M. Boyett, Ching-Hon Pui, Mary V. Relling
Journal: Journal of Clinical Oncology (2003)

Purpose: To study the pharmacokinetics and pharmacodynamics of once- versus twice-daily oral etoposide in children with relapsed or refractory acute lymphoblastic leukemia (ALL). Patients and Methods: Fifty-eight patients were randomly assigned to etoposide at 50 mg/m 2 /d with once- versus twice-daily doses for 22 days. On day 8, vincristine, asparaginase, and dexamethasone were started. Etoposide pharmacokinetics and pharmacodynamics were studied for 47, 28, and 26 patients on day 1, 8, and 22, respectively, of remission reinduction therapy. Results: Of 48 patients with pharmacokinetic data, 42 (87.5%) achieved complete remission, three (6.3%) failed to achieve remission, and three (6.3%) died during induction. Median etoposide day 8 area under concentration-time curve (AUC) and cumulative AUC tended to be greater (P = .06 and P = .07, respectively) in patients (n = 23) who achieved complete remission (24 and 522 μmol/L • h, respectively) than in patients (n = 3) who did not (14 and 303 μmol/L • h, respectively). Three of eight patients with plasma concentrations exceeding 1.7 μM (1 μg/mL) for more than 8 hours daily, compared with one of 20 patients with concentrations exceeding 1.7 μM for ≤ 8 hours daily, were unable to receive all 22 days of etoposide because of toxicity. There was no difference in the AUC at day 1 or day 8 with once- versus twice-daily doses (P = .55 and P = .86, respectively). Conclusion: A pharmacodynamic relationship exists between systemic etoposide exposure and response to therapy when oral etoposide is used as part of remission induction regimens for relapsed or refractory childhood ALL.
Fatty kidney: emerging role of ectopic lipid in obesity-related renal disease
Authors: Aiko P J de Vries, Piero Ruggenenti, Xiong Z Ruan, Manuel Praga, Josep M Cruzado, Ingeborg M Bajema, Vivette D D'Agati, Hildo J Lamb, Drazenka Pongrac Barlovic, Radovan Hojs, Manuela Abbate, Rosa Rodriquez, Carl Erik Mogensen, Esteban Porrini
Journal: The Lancet Diabetes & Endocrinology (2014)
Targeting Apoptosis Pathways for New Cancer Therapeutics
Authors: Longchuan Bai, Shaomeng Wang
Journal: Annual Review of Medicine (2013)

The past decade has witnessed tremendous advances in the discovery and development of novel small-molecule inhibitors targeting apoptosis pathways for cancer treatment, with some compounds now in clinical development. Early promising clinical data have been reported with these new classes of anticancer drugs. This review highlights the recent advancements in the development of small-molecule inhibitors targeting three major classes of antiapoptotic proteins: antiapoptotic B cell lymphoma 2 (BCL-2) proteins, inhibitor of apoptosis proteins (IAPs), and murine double-minute 2 (MDM2). Special emphasis is given to those that have been advanced into clinical trials. The challenges and future directions in the further preclinical and clinical development of these new anticancer drugs are also discussed.
Vascular Endothelial Growth Factor Genotypes, Haplotypes, Gender, and the Risk of Non–Small Cell Lung Cancer
Authors: Rihong Zhai, Geoffrey Liu, Wei Zhou, Li Su, Rebecca Suk Heist, Thomas J. Lynch, John C. Wain, Kofi Asomaning, Xihong Lin, David C. Christiani
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis involving tumor growth and metastasis. Polymorphisms in the VEGF gene may regulate VEGF production. In this large case-control study, we investigated whether functional polymorphisms (−460C/T, +405C/G, +936C/T) in the VEGF gene are associated with the risk of non–small cell lung cancer (NSCLC). Experimental Design:VEGF genotypes and haplotypes were determined in 1,900 Caucasian patients with NSCLC and 1,458 healthy controls. The results were analyzed using logistic regression models, adjusting for age, gender, smoking status, pack-years of smoking, and years since smoking cessation (for ex-smokers). The false-positive report probability was estimated for the observed odds ratios (OR). Results: There were no overall associations between individual VEGF genotypes and the risk of NSCLC. Stratified analysis suggested that the combined +405CC+CG genotype was significantly associated with increased risk of lung adenocarcinoma in males (adjusted OR, 1.40; 95% confidence interval, 1.03-1.87). In haplotype analysis, haplotypes were globally associated with differences between cases and controls in males (P = 0.03). Specifically, the −460T/+405G/+936C haplotype was significantly (P = 0.02) associated with decreased risk of adenocarcinoma in males when compared with the most common CGC haplotype (adjusted OR, 0.76; 95% confidence interval, 0.50-0.98). None of the VEGF genotypes and haplotypes studied significantly influenced the susceptibility to NSCLC in females. Conclusions: Polymorphisms of −460C/T, +405C/G, and +936C/T in the VEGF gene do not play a major role in NSCLC risk. However, we could not exclude a minor role for the +405CC+CG genotypes and the 460T/+405G/+936C haplotype in lung adenocarcinogenesis in male Caucasians.
Disruption of KCC2 Reveals an Essential Role of K-Cl Cotransport Already in Early Synaptic Inhibition
Authors: Christian A. Hübner, Valentin Stein, Irm Hermans-Borgmeyer, Torsten Meyer, Klaus Ballanyi, Thomas J. Jentsch
Journal: Neuron (2001)

In fetal life and early postnatal development, both Martinistr.52 neurotransmitters act mostly excitatory because the in-D-20246 Hamburg tracellular chloride concentration is above equilibrium.Germany The excitatory action of GABA in the immature CNS is 2 Zentrum fu ¨r Physiologie und Pathophysiologie believed to be important for the development of the Universita ¨t Go ¨ttingen nervous system, as it may exert a trophic action through Humboldtallee 23 membrane depolarization and an ensuing rise in intra-D-37073 Go ¨ttingen cellular Ca 2ϩ (Cherubini et al., 1991; LoTurco et al., 1995; Germany Yuste and Katz, 1991).Since glutamatergic synaptic transmission is first purely NMDA receptor based, the depolarization by GABA may be necessary to provide Summary the initial depolarization that is needed to relieve the voltage-dependent Mg 2ϩ block of NMDA receptors Synaptic inhibition by GABA A and glycine receptors, (Ben-Ari et al., 1997).During the maturation of the CNS, which are ligand-gated anion channels, depends on there is a widespread decrease of neuronal [Cl Ϫ ] i , which the electrochemical potential for chloride.Several pois finally below its equilibrium, so that the opening of tassium-chloride cotransporters can lower the intrathe GABA A or the glycine receptor leads to an inflow of cellular chloride concentration [Cl Ϫ ] i , including the Cl Ϫ and an inhibitory hyperpolarization of the cell.The neuronal isoform KCC2.We show that KCC2 knockout most important players are probably members of the mice died immediately after birth due to severe motor cation-chloride cotransporter gene family.This family deficits that also abolished respiration.Sciatic nerve includes the Na-Cl cotransporter (NCC), the Na-K-2Cl recordings revealed abnormal spontaneous electrical cotransporters (NKCC), which typically raise [Cl Ϫ ] i , and activity and altered spinal cord responses to periph-K-Cl cotransporters (KCCs), which normally lower [Cl Ϫ ] i eral electrical stimuli.In the spinal cord of wild-type below its electrochemical equilibrium potential.Consisanimals, the KCC2 protein was found at inhibitory syntent with their differential tissue distributions, their funcapses.Patch-clamp measurements of embryonic day tion is not restricted to regulate neuronal [Cl Ϫ ] i .Several 18.5 spinal cord motoneurons demonstrated an excitof these transporters play important roles in transepitheatory GABA and glycine action in the absence, but not lial transport and cell volume regulation.These functions in the presence, of KCC2, revealing a crucial role of are demonstrated by diseases that result from mutations KCC2 for synaptic inhibition. in their genes.Mutations in NCC and NKCC2 underlie Gitelman's syndrome (Simon et al., 1996b) or a form of
Development and Preclinical Characterization of a Humanized Antibody Targeting CXCL12
Authors: Cuiling Zhong, Jianyong Wang, Bing Li, Hong Xiang, Mark Ultsch, Mary Coons, Terence Wong, Nancy Y. Chiang, Suzy Clark, Robyn Clark, Leah Quintana, Peter Gribling, Eric Suto, Kai Barck, Racquel Corpuz, Jenny Yao, Rashi Takkar, Wyne P. Lee, Lisa A. Damico-Beyer, Richard D. Carano, Camellia Adams, Robert F. Kelley, Weiru Wang, Napoleone Ferrara
Journal: Clinical Cancer Research (2013)

Our goal was to develop a potent humanized antibody against mouse/human CXCL12. This report summarized its in vitro and in vivo activities.Cell surface binding and cell migration assays were used to select neutralizing hamster antibodies, followed by testing in several animal models. Monoclonal antibody (mAb) 30D8 was selected for humanization based on its in vitro and in vivo activities.30D8, a hamster antibody against mouse and human CXCL12α, CXCL12β, and CXCL12γ, was shown to dose-dependently block CXCL12α binding to CXCR4 and CXCR7, and CXCL12α-induced Jurkat cell migration in vitro. Inhibition of primary tumor growth and/or metastasis was observed in several models. 30D8 alone significantly ameliorated arthritis in a mouse collagen-induced arthritis model (CIA). Combination with a TNF-α antagonist was additive. In addition, 30D8 inhibited 50% of laser-induced choroidal neovascularization (CNV) in mice. Humanized 30D8 (hu30D8) showed similar in vitro and in vivo activities as the parental hamster antibody. A crystal structure of the hu30D8 Fab/CXCL12α complex in combination with mutational analysis revealed a "hot spot" around residues Asn(44)/Asn(45) of CXCL12α and part of the RFFESH region required for CXCL12α binding to CXCR4 and CXCR7. Finally, hu30D8 exhibited fast clearance in cynomolgus monkeys but not in rats.CXCL12 is an attractive target for treatment of cancer and inflammation-related diseases; hu30D8 is suitable for testing this hypothesis in humans.
The falling incidence and prevalence of dermatitis herpetiformis
Authors: L. Fry
Journal: British Journal of Dermatology (2011)

Journal Article The falling incidence and prevalence of dermatitis herpetiformis Get access L. Fry L. Fry Room G3, St Mary's Campus, Imperial College, London W2 1PG, U.K. E‐mail: l.fry@imperial.co.uk Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 165, Issue 2, 1 August 2011, Page 229, https://doi.org/10.1111/j.1365-2133.2011.10460.x Published: 01 August 2011
Simple Rapid Methods of Estimating Arterial and Mixed Venous pCO2
Authors: E. J. M. Campbell, J. B. L. Howell
Journal: BMJ (1960)

MEDICAL JOURNAL over into the absorber and back 10-15 times; allow the mercury to fall until KOH level returns to zero (this is accomplished by using the cock (C) to regulate rate of fall and the screw clip (S) for final fine adjustment); read the % CO, off the burette; repeat passage to check that absorption is complete.The analysis takes less than two minutes from start to finish.Accuracy.-Serialanalyses are reproducible to within L 0.05%.Several comparisons both with the standard Haldane and with Lloyd's modification (Lloyd, 1958) gave agreement which was usually within ±0.05% and never outside 0.1 %.This degree of accuracy is more than adequate for the purpose for which the instrument is intended.Modified Instrument The insert shows an alternative arrangement which, at the expense of the complexity of two taps instead of one, slightly speeds up the analyses and facilitates servicing.The calibrated volume includes the bores of the two taps and the connecting tube.The instrument is left with tap 1 (T) and tap 2 (1); turn tap 2 (F-o) and adjust KOH level to zero.Tap 2 is then turned ( J ); the mercury is forced up into the stem of tap 1 and the sample of air is flushed through both taps; tap 1 is turned ( ^3) and the sample is introduced to 0 (10 ml.); tap 1 is turned (H ); tap 2 is turned ( <-); the zero level is checked, and absorption carried out as described above, Cleaning through with acid can be done with tap 2 (I) without needing to empty the KOH from the absorption pipette.I am grateful to Dr.
Evaluation of carotid artery and aortic intima-media thickness measurements for exclusion of significant coronary atherosclerosis in patients scheduled for heart valve surgery
Authors: Laurent Belhassen, Claudine Carville, Gabriel Pelle, Jean Luc Monin, Emmanuel Teiger, Anne-Marie Duval-Moulin, Patrick Dupouy, Jean Luc Dubois Rande, Pascal Gueret
Journal: Journal of the American College of Cardiology (2002)
Oligodendroglioma cell lines containing t(1;19)(q10;p10)
Authors: J. J. P. Kelly, M. D. Blough, O. D. M. Stechishin, J. A. W. Chan, D. Beauchamp, M. Perizzolo, D. J. Demetrick, L. Steele, R. N. Auer, W. J. Hader, M. Westgate, I. F. Parney, R. Jenkins, J. G. Cairncross, S. Weiss
Journal: Neuro-Oncology (2010)

Investigating the biology of oligodendroglioma and its characteristic combined deletion of chromosomal arms 1p and 19q, mediated by an unbalanced translocation, t(1;19)(q10;p10), has been hampered by the lack of cell lines that harbor these traits. We grew cells from 2 anaplastic oligodendrogliomas in serum-free conditions. Serial propagation and expansion led to the establishment of permanent cell lines that maintained the genetic signature of the parent oligodendrogliomas and displayed features of brain tumor stem cells in vitro. One line was established from a treatment-naïve tumor and the other from a temozolomide resistant recurrent tumor. These lines may be important tools for understanding the biology of oligodendrogliomas and the function of their defining genetic traits.
Childhood asthma is associated with mutations and gene expression differences of <i><scp>ORMDL</scp></i> genes that can interact
Authors: A. A. Toncheva, D. P. Potaczek, M. Schedel, S. W. Gersting, S. Michel, N. Krajnov, V. D. Gaertner, J. M. Klingbeil, T. Illig, A. Franke, C. Winkler, J. M. Hohlfeld, C. Vogelberg, A. von Berg, A. Bufe, A. Heinzmann, O. Laub, E. Rietschel, B. Simma, J. Genuneit, A. C. Muntau, M. Kabesch
Journal: Allergy (2015)

Genomewide association studies identified ORMDL3 as a plausible asthma candidate gene. ORMDL proteins regulate sphingolipid metabolism and ceramide homeostasis and participate in lymphocyte activation and eosinophil recruitment. Strong sequence homology between the three ORMDL genes and ORMDL protein conservation among different species suggest that they may have shared functions. We hypothesized that if single nucleotide polymorphisms (SNPs) in ORMDL3 alter its gene expression and play a role in asthma, variants in ORMDL1 and ORMDL2 might also be associated with asthma.Asthma associations of 44 genotyped SNPs were determined in at least 1303 subjects (651 asthmatics). ORMDL expression was evaluated in peripheral blood mononuclear cells (PBMC) from 55 subjects (eight asthmatics) before and after allergen stimulation, and in blood (n = 60, 5 asthmatics). Allele-specific cis-effects on ORMDL expression were assessed. Interactions between human ORMDL proteins were determined in living cells.Sixteen SNPs in all three ORMDLs were associated with asthma (14 in ORMDL3). Baseline expression of ORMDL1 (P = 1.7 × 10(-6) ) and ORMDL2 (P = 4.9 × 10(-5) ) was significantly higher in PBMC from asthmatics, while induction of ORMDLs upon stimulation was stronger in nonasthmatics. Disease-associated alleles (rs8079416, rs4795405, rs3902920) alter ORMDL3 expression. ORMDL proteins formed homo- and heterooligomers and displayed similar patterns of interaction with SERCA2 and SPT1.Polymorphisms in ORMDL genes are associated with asthma. Asthmatics exhibit increased ORMDL levels, suggesting that ORMDLs contribute to asthma. Formation of heterooligomers and similar interaction patterns with proteins involved in calcium homeostasis and sphingolipid metabolism could indicate shared biological roles of ORMDLs, influencing airway remodeling and hyperresponsiveness.
Potential Animal Models for Senile Dementia of Alzheimer's Type, with Emphasis on AF64A-Induced Cholinotoxicity
Authors: A Fisher, I Hanin
Journal: The Annual Review of Pharmacology and Toxicology (1986)

Over the past two decades, deadly coronaviruses, with the most recent being the severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) 2019 pandemic, have majorly challenged public health. The path for virus invasion into humans and other ...Read More
Inflammatory Mechanisms in Obesity
Authors: Margaret F. Gregor, Gökhan S. Hotamisligil
Journal: Annual Review of Immunology (2011)

The modern rise in obesity and its strong association with insulin resistance and type 2 diabetes have elicited interest in the underlying mechanisms of these pathologies. The discovery that obesity itself results in an inflammatory state in metabolic tissues ushered in a research field that examines the inflammatory mechanisms in obesity. Here, we summarize the unique features of this metabolic inflammatory state, termed metaflammation and defined as low-grade, chronic inflammation orchestrated by metabolic cells in response to excess nutrients and energy. We explore the effects of such inflammation in metabolic tissues including adipose, liver, muscle, pancreas, and brain and its contribution to insulin resistance and metabolic dysfunction. Another area in which many unknowns still exist is the origin or mechanism of initiation of inflammatory signaling in obesity. We discuss signals or triggers to the inflammatory response, including the possibility of endoplasmic reticulum stress as an important contributor to metaflammation. Finally, we examine anti-inflammatory therapies for their potential in the treatment of obesity-related insulin resistance and glucose intolerance.
Serum Lipids and the Progression of Nephropathy in Type 1 Diabetes
Authors: Merlin C. Thomas, Milla Rosengård-Bärlund, Vashti Mills, Mats Rönnback, Stephen Thomas, Carol Forsblom, Mark E. Cooper, Marja-Riitta Taskinen, Giancarlo Viberti, Per-Henrik Groop
Journal: Diabetes Care (2006)

OBJECTIVE—Dyslipidemia contributes to the progression of microvascular disease in diabetes. However, different lipid variables may be important at different stages of nephropathy. This study examines the pattern of dyslipidemia associated with the progression of nephropathy in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS—A total of 152 patients with type 1 diabetes were recruited in order to represent various phases of nephropathy. Patients were followed for 8–9 years, during which time they received standard care. Renal progression was defined a priori as a doubling in albumin excretion (in patients with normo- or microalbuminuria) or a decline in creatinine clearance (in those with macroalbuminuria). A panel of lipid variables was determined and correlated with indexes of progression. RESULTS—In patients with normoalbuminuria (n = 66), progression was associated with male sex (P &amp;lt; 0.05), borderline albuminuria (P = 0.02), and LDL-free cholesterol (P = 0.02). In patients with microalbuminuria (n = 51), progression was independently associated with triglyceride content of VLDL and intermediate-density lipoprotein (both P &amp;lt; 0.05). In patients with macroalbuminuria (n = 36), a significant decline in the renal function (&amp;gt;3 ml · min−1 · year−1) was independently associated with poor glycemic control, hypertension, and LDL size (P &amp;lt; 0.05). When all patients with progressive nephropathy were analyzed together, only LDL cholesterol was predictive on multivariate analysis (P &amp;lt; 0.05), which masked the importance of triglyceride enrichment in microalbuminuria. CONCLUSIONS—Lipid variables are associated with progression of diabetic kidney disease, but the relationship is not the same at all stages. This finding has implications for the design of renoprotective strategies and the interpretation of clinical trials in type 1 diabetes.
V. THE IRON CONTENT OF BLOOD FREE TISSUES AND VISCERA
Authors: Robert P. Bogniard, George H. Whipple
Journal: The Journal of Experimental Medicine (1932)

When hemoglobin is set free in the circulation the kidney plays an important part in the conservation of iron. When the renal threshold is not exceeded by the hemoglobin in the blood there is little or no excess iron deposited in the kidney but when superthreshold doses of blood hemoglobin are given the epithelium of the convoluted tubules accumulates much iron and the iron analyses may show 5 times normal values. The normal dog (140 to 150 per cent hemoglobin) has a large reserve store of iron in the liver, spleen and marrow. Diets may modify this storage of iron in these tissues. To bring conclusive proof relating to the individual diet factors, the reserve store of iron should be depleted by an anemia period of 2 to 3 months. Complete removal of red cells from tissue capillaries is essential for accurate iron assays of fresh tissue. The method described accomplishes this without causing gross tissue edema. The lowest iron content is observed in the pancreas, stomach, jejunum, colon and urinary bladder. These figures average from 1 to 2 mg. iron per 100 gm. fresh tissue. This shows that smooth muscle and mucous membranes contain little iron. Striated muscle (heart, psoas) shows a relatively low iron content but uniform values close to 4 mg. per 100 gm. tissue. Lungs show a considerable fluctuation with low iron values in anemia (3.7 mg.) and higher values in health (6 to 7 mg.). The spleen shows maximal fluctuations and the highest reserve storage of iron per 100 gm. fresh tissue. The spleen iron analyses show low values in anemia (7 to 15 mg.) and wide differences in controls (25 to 50 mg.). With hemoglobin injections the iron storage is conspicuous and iron analyses may run as high as l50 to 175 mg. iron per 100 gm. fresh tissue. Bone marrow of the rib runs in parallel with the spleen as regards iron storage following hemoglobin injections and depletion following anemia periods. The liver because of its weight always contains the main bulk of the iron stored in the blood free tissues of the body. Its store is depleted by anemia even to levels of 4 to 5 mg. iron per 100 gm. fresh tissue. In the normal dog the iron store in the liver averages 25 mg. per 100 gm. tissue. Frequent hemoglobin injections may increase this level to 31 mg. iron per 100 gm. The liver is considered the most active clearing house for iron storage and utilization.
Gitelman's syndrome (Bartter's variant) maps to the thiazide-sensitive cotransporter gene locus on chromosome 16q13 in a large kindred.
Authors: M R Pollak, V B Delaney, R M Graham, S C Hebert
Journal: Journal of the American Society of Nephrology (1996)

A defect in distal renal tubular sodium chloride handling is thought to be responsible for the clinical phenotype of Gitelman's syndrome, a variant of Bartter's syndrome. To study the possible involvement of the renal thiazide-sensitive NaCl cotransporter gene in the syndrome, a linkage analysis study in the largest reported kindred with the syndrome was performed. A human homolog of rat thiazide-sensitive cotransporter was cloned and mapped to chromosome 16q13 by fluorescent in situ hybridization. All 17 family members in two generations were genotyped at loci in this region. There were no recombinants observed between the Gitelman's syndrome phenotype and inheritance of D16S408 alleles, yielding a lod score of 3.88 at Q = 0. By contrast, recombinants were observed between Gitelman's syndrome and the flanking markers D16S419 and D16S400, localizing the responsible gene in this family to a 15 centimorgan region on chromosome 16q. These genetic data, together with current understanding of the molecular physiology of the thiazide-sensitive cotransporter, are strong evidence that the latter is defective in this kindred with Gitelman's syndrome.