tbuckley/cabot-search huggingface dataset:
Endocrine outcome in children with medulloblastoma treated with 18 Gy of craniospinal radiation therapy
Authors: Weizhen Xu, Anna Janss, Roger J. Packer, Peter Phillips, Joel Goldwein, Thomas Moshang
Journal: Neuro-Oncology (2004)

Craniospinal radiation therapy (CSRT) combined with chemotherapy results in significant endocrine morbidity. Between 1987 and 1990, a trial using 18 Gy was conducted to treat 10 young children with medulloblastoma. There were 7 survivors. We compared the endocrine outcome in these children (group 18 Gy) to that of a comparable group treated with conventional doses of CSRT that ranged from 23 to 39 Gy (group CD). Both groups had an identical history of chemotherapy and tumor stage and were treated with recombinant growth hormone therapy (rhGH). The mean age of group 18 Gy at diagnosis was 4.0 years, and rhGH treatment was initiated in 6 children at age 9.2 years. Group CD (12 children) was diagnosed at a mean age of 5.8 years and rhGH started in 11 children at a mean age of 9.6 years. The dose of rhGH used in both groups was identical (0.3 mg/kg/wk). For group 18 Gy, adult heights and sitting heights (a mean standard deviation score of -1.01 ± 1.11 and -1.62 ± 1.16, respectively) were statistically greater (P < 0.05) than those for group CD (mean standard deviation score of -2.04 ± 0.83 and -3.16 ± 1.43, respectively). Moreover, adult heights of group 18 Gy were not different from midparental heights, unlike group CD, whose adult heights were less than midparental heights (P < 0.0001). Of other endocrine sequelae, 10 patients of the CD group were hypothyroid, 3 had adrenal insufficiency, 3 had hypogonadism, and 2 had early puberty. In contrast, within group 18 Gy, only 1 was hypothyroid (P = 0.006) and 1 had early puberty. We conclude that endocrine morbidity was significantly reduced with 18 Gy CSRT in young children with medulloblastoma.
Structural determinants of human ζ-globin mRNA stability
Authors: Zhenning He, Decheng Song, Sebastiaan van Zalen, J Eric Russell
Journal: Journal of Hematology & Oncology (2014)

The normal accumulation of adult α and β globins in definitive erythrocytes is critically dependent upon processes that ensure that the cognate mRNAs are maintained at high levels in transcriptionally silent, but translationally active progenitor cells. The impact of these post-transcriptional regulatory events on the expression of embryonic ζ globin is not known, as its encoding mRNA is not normally transcribed during adult erythropoiesis. Recently, though, ζ globin has been recognized as a potential therapeutic for α thalassemia and sickle-cell disease, raising practical questions about constitutive post-transcriptional processes that may enhance, or possibly prohibit, the expression of exogenous or derepresssed endogenous ζ-globin genes in definitive erythroid progenitors. The present study assesses mRNA half-life in intact cells using a pulse-chase approach; identifies cis-acting determinants of ζ-globin mRNA stability using a saturation mutagenesis strategy; establishes critical 3′UTR secondary structures using an in vitro enzymatic mapping method; and identifies trans-acting effector factors using an affinity chromatographical procedure. We specify a tetranucleotide 3′UTR motif that is required for the high-level accumulation of ζ-globin transcripts in cultured cells, and formally demonstrate that it prolongs their cytoplasmic half-lives. Surprisingly, the ζ-globin mRNA stability motif does not function autonomously, predicting an activity that is subject to structural constraints that we subsequently specify. Additional studies demonstrate that the ζ-globin mRNA stability motif is targeted by AUF1, a ubiquitous RNA-binding protein that enhances the half-life of adult β-globin mRNA, suggesting commonalities in post-transcriptional processes that regulate globin transcripts at all stages of mammalian development. These data demonstrate a mechanism for ζ-globin mRNA stability that exists in definitive erythropoiesis and is available for therapeutic manipulation in α thalassemia and sickle-cell disease.
Hazardous Benzodiazepine Regimens in the Elderly: Effects of Half-Life, Dosage, and Duration on Risk of Hip Fracture
Authors: Philip S. Wang, Rhonda L. Bohn, Robert J. Glynn, Helen Mogun, Jerry Avorn
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: While benzodiazepine treatment is known to increase the risk of hip fracture in older populations, controversy persists over which characteristics of benzodiazepine use (e.g., elimination half-life, dosage, duration of use) are most associated with such risks. METHOD: The authors reviewed the health care utilization data of 1,222 hip fracture patients and 4,888 comparison patients frequency matched on the basis of age and gender (all were at least 65 years old). Patients were enrolled in Medicare as well as in the New Jersey Medicaid or Pharmaceutical Assistance to the Aged and Disabled programs. Benzodiazepine use, as well as other covariates, were assessed before the index date (which was either the date of hospital admission for hip fracture surgical repair or, for the comparison subjects, a randomly assigned, frequency-matched date). RESULTS: All benzodiazepine doses ≥3 mg/day in diazepam equivalents significantly increased the adjusted risk of hip fracture by 50%. Significantly increased adjusted risks of hip fracture were seen during the initial 2 weeks of use (60% increase) and after more than 1 month of continuous use (80% increase) but not for 2–4 weeks of continuous use. Use of benzodiazepines other than long-acting agents significantly increased the risk of hip fracture by 50%. CONCLUSIONS: Even at modest doses, including some low doses currently advocated in prescribing guidelines for older patients, treatment with benzodiazepines appears to increase the risk of hip fracture. Patients appear to be particularly vulnerable immediately after initiating therapy and after more than 1 month of continuous use. Benzodiazepines with shorter half-lives appear to be no safer than longer half-life agents. Clinicians should be aware of these risks and weigh them against potential benefits when prescribing for elderly patients.
Black/White Disparities in Receipt of Treatment and Survival Among Men With Early-Stage Breast Cancer
Authors: Helmneh M. Sineshaw, Rachel A. Freedman, Elizabeth M. Ward, W. Dana Flanders, Ahmedin Jemal
Journal: Journal of Clinical Oncology (2015)

Purpose To examine the extent of black/white disparities in receipt of treatment and survival for early-stage breast cancer in men age 18 to 64 and ≥ 65 years. Patients and Methods We identified 725 non-Hispanic black (black) and 5,247 non-Hispanic white (white) men diagnosed with early-stage breast cancer from 2004 to 2011 in the National Cancer Data Base. We used multivariable logistic regression and calculated standardized risk ratios to predict receipt of treatment and a proportional hazards model to estimate overall hazard ratios (HRs) in black versus white men age 18 to 64 and ≥ 65 years, separately. Results Receipt of treatment was remarkably similar between blacks and whites in both age groups. Black and white older men had lower receipt of chemotherapy (39.2% and 42.0%, respectively) compared with younger patients (76.7% and 79.3%, respectively). Younger black men had a 76% higher risk of death than younger white men after adjustment for clinical factors only (HR, 1.76; 95% CI, 1.11 to 2.78), but this difference significantly diminished after subsequent adjustment for insurance and income (HR, 1.37; 95% CI, 0.83 to 2.24). In those age ≥ 65 years, the excess risk of death in blacks versus whites was nonsignificant and not affected by adjustment for covariates. Conclusion The excess risk of death in black versus white men diagnosed with early-stage breast cancer was largely confined to those age 18 to 64 years and became nonsignificant after adjustment for differences in insurance and income. These findings suggest the importance of improving access to care in reducing racial disparities in male breast cancer mortality.
Modeling Interpatient Pharmacodynamic Variability of Etoposide
Authors: Rosemarie Mick, Mark J. Ratain
Journal: JNCI Journal of the National Cancer Institute (1991)

This report describes approaches to modeling interpatient pharmacodynamic variability of etoposide effect as measured by white blood cell count nadir. Such models may be utilized in adaptive control dosing to individualize the dose administered to a patient with the aim of lessening the risk of severe myelosuppression. We have successfully employed adaptive control dosing of etoposide administered by 72-hour continuous infusion based on our prior pharmacodynamic model for white blood cell count nadir. Data from our most recent series of 41 patients were used to investigate new linear and nonlinear pharmacodynamic models. We then cross-validated our best models on data from an independent series of 27 similarly treated patients. We identified an unbiased model that exhibited high precision in both data sets (root mean square errors of 1.11 x 10(3) and 1.20 x 10(3) cells/microL, respectively). The optimal model was a nonlinear Hill model defined by 24-hour etoposide concentration, pretreatment white blood cell count, and pretreatment serum albumin level. The level of albumin was found to be both a component of kinetic (protein binding) and dynamic (patient health) variability. Patients with lower pretreatment albumin levels are at higher risk of severe myelosuppression during etoposide therapy.
The relationship between glomerular filtration rate and sodium reabsorption by the proximal tubule of the rat nephron
Authors: Barry M. Brenner, Cleaves M. Bennett, Robert W. Berliner
Journal: Journal of Clinical Investigation (1968)

We have tested two of the hypotheses proposed to explain the adjustment in sodium reabsorption in the proximal tubule that follows a change in the rate of glomerular filtration (glomerulotubular balance). Using the recollection micropuncture technique, we were able to measure the immediate and late changes in reabsorptive rate after an acute alteration in filtration rate produced by aortic constriction and release of constriction. It was found that fractional reabsorption, as measured by the inulin tubule fluid to plasma (TF/P) ratio, increased after aortic constriction and decreased after release, but that in most instances, absolute reabsorptive rate changed in parallel to glomerular filtration rate. The change was similar whether the collections were made less than 1 or more than 5 min after the change in blood pressure. The rapid time course of this adjustment in reabsorptive rate is viewed as evidence against an intrarenal humoral feedback mechanism. In the same experiments we measured the (TF/P)(In), transit time, and flow rate of fluid in single nephrons before and during aortic constriction or release of aortic constriction. The change in reabsorptive rate and the simultaneous change in calculated cross-sectional area of the tubule lumen were rarely proportional, i.e., C/pir(2) was not constant. In other experiments, these same measurements were made before and during periods of increased ureteral pressure. Despite large increments in calculated cross-sectional area, the absolute rate of reabsorption either remained relatively unchanged or fell in proportion to the change in filtration rate. It is concluded that under these conditions, reabsorptive rate is governed by some factor other than tubule geometry.
Phase 1 Study of Valproic Acid in Pediatric Patients with Refractory Solid or CNS Tumors: A Children's Oncology Group Report
Authors: Jack M. Su, Xiao-Nan Li, Patrick Thompson, Ching-Nan Ou, Ashish M. Ingle, Heidi Russell, Ching C. Lau, Peter C. Adamson, Susan M. Blaney
Journal: Clinical Cancer Research (2010)

Abstract Purpose: The primary purpose of this trial was to define and describe the toxicities of oral valproic acid (VPA) at doses required to maintain trough concentrations of 100 to 150 mcg/mL or 150 to 200 mcg/mL in children with refractory solid or central nervous system (CNS) tumors. Secondary objectives included assessment of free and total VPA pharmacokinetics (PKs) and histone acetylation in peripheral blood mononuclear cells (PBMC) at steady state. Patients and Methods: Oral VPA, initially administered twice daily and subsequently three times daily, was continued without interruption to maintain trough concentrations of 100 to 150 mcg/mL. First-dose and steady-state PKs were studied. Histone H3 and H4 acetylation in PBMCs was evaluated using an ELISA technique. Results: Twenty-six children, sixteen of whom were evaluable for toxicity, were enrolled. Dose-limiting somnolence and intratumoral hemorrhage were associated with VPA troughs of 100 to 150 mcg/mL. Therefore, the final cohort of six children received VPA to maintain troughs of 75 to 100 mcg/mL and did not experience any dose-limiting toxicity. First-dose and steady-state VPA PK parameters were similar to values previously reported in children with seizures. Increased PBMC histone acetylation was documented in 50% of patients studied. One confirmed partial response (glioblastoma multiforme) and one minor response (brainstem glioma) were observed. Conclusions: VPA administered three times daily to maintain trough concentrations of 75 to 100 mcg/mL was well tolerated in children with refractory solid or CNS tumors. Histone hyperacetylation in PBMCs was observed in half of the patients at steady state. Future trials combining VPA with chemotherapy and/or radiation therapy should be considered, especially for CNS tumors. Clin Cancer Res; 17(3); 589–97. ©2010 AACR.
The NF-κB subunit Rel A is associated with in vitro survival and clinical disease progression in chronic lymphocytic leukemia and represents a promising therapeutic target
Authors: Saman Hewamana, Suhair Alghazal, Thet Thet Lin, Matthew Clement, Chris Jenkins, Monica L. Guzman, Craig T. Jordan, Sundar Neelakantan, Peter A. Crooks, Alan K. Burnett, Guy Pratt, Chris Fegan, Clare Rowntree, Paul Brennan, Chris Pepper
Journal: Blood (2008)
The thymic medulla is required for Foxp3+ regulatory but not conventional CD4+ thymocyte development
Authors: Jennifer E. Cowan, Sonia M. Parnell, Kyoko Nakamura, Jorge H. Caamano, Peter J.L. Lane, Eric J. Jenkinson, William E. Jenkinson, Graham Anderson
Journal: The Journal of Experimental Medicine (2013)

A key role of the thymic medulla is to negatively select autoreactive CD4+ and CD8+ thymocytes, a process important for T cell tolerance induction. However, the involvement of the thymic medulla in other aspects of αβ T cell development, including the generation of Foxp3+ natural regulatory T cells (nTreg cells) and the continued maturation of positively selected conventional αβ T cells, is unclear. We show that newly generated conventional CD69+Qa2− CD4 single-positive thymocytes mature to the late CD69−Qa2+ stage in the absence of RelB-dependent medullary thymic epithelial cells (mTECs). Furthermore, an increasing ability to continue maturation extrathymically is observed within the CD69+CCR7−/loCCR9+ subset of conventional SP4 thymocytes, providing evidence for an independence from medullary support by the earliest stages after positive selection. In contrast, Foxp3+ nTreg cell development is medullary dependent, with mTECs fostering the generation of Foxp3−CD25+ nTreg cell precursors at the CD69+CCR7+CCR9− stage. Our results demonstrate a differential requirement for the thymic medulla in relation to CD4 conventional and Foxp3+ thymocyte lineages, in which an intact mTEC compartment is a prerequisite for Foxp3+ nTreg cell development through the generation of Foxp3−CD25+ nTreg cell precursors.
Effect of Alterations in the Stimulus Rate upon Energy Output, Tension Development and Tension-Time Integral of Cardiac Muscle in Rabbits
Authors: C. L. GIBBS, W. R. GIBSON
Journal: Circulation Research (1970)

The effect of stimulus rate on the isometric energy output of rabbit papillary muscle at room temperature was examined by a myothermic technique. The stimulus rates used were: 1 per 1.5, 2.0, 3.0, 7.0 and 10.0 seconds. Mechanical output at any given rate was varied by altering muscle length. Both peak tension and the time integral of tension were used as mechanical variables against which isometric heat production was plotted. The relationship between heat and peak tension was curvilinear, whereas that between heat and the time integral of tension was rectilinear. Statistically either mechanical index was equally good at predicting isometric heat production. Changes in the stimulus rate did not affect any of the parameters (intercept, slope, curvature) of the polynomials relating heat to tension but increasing the stimulus rate did significantly raise the slope of the relationships between heat and the time integral of tension. The magnitude of the tension-independent heat rose from .596 mcal/g muscle at a stimulus rate of 1 per 10 seconds to 0.744 mcal/g at a rate of 1 per 1.5 seconds.
Methylation-Independent Silencing of the Tumor Suppressor <i>INK4b</i> (p15) by CBFβ-SMMHC in Acute Myelogenous Leukemia with inv(16)
Authors: Jan Markus, Matthew T. Garin, Juraj Bies, Naomi Galili, Azra Raza, Michael J. Thirman, Michelle M. Le Beau, Janet D. Rowley, P. Paul Liu, Linda Wolff
Journal: Cancer Research (2007)

Abstract The tumor suppressor gene INK4b (p15) is silenced by CpG island hypermethylation in most acute myelogenous leukemias (AML), and this epigenetic phenomenon can be reversed by treatment with hypomethylating agents. Thus far, it was not investigated whether INK4b is hypermethylated in all cytogenetic subtypes of AML. A comparison of levels of INK4b methylation in AML with the three most common cytogenetic alterations, inv(16), t(8;21), and t(15;17), revealed a strikingly low level of methylation in all leukemias with inv(16) compared with the other types. Surprisingly, the expression level of INK4b in inv(16)+ AML samples was low and comparable with that of the other subtypes. An investigation into an alternative mechanism of INK4b silencing determined that the loss of INK4b expression was caused by inv(16)-encoded core binding factor β-smooth muscle myosin heavy chain (CBFβ-SMMHC). The silencing was manifested in an inability to activate the normal expression of INK4b RNA as shown in vitamin D3–treated U937 cells expressing CBFβ-SMMHC. CBFβ-SMMHC was shown to displace RUNX1 from a newly determined CBF site in the promoter of INK4b. Importantly, this study (a) establishes that the gene encoding the tumor suppressor p15INK4b is a target of CBFβ-SMMHC, a finding relevant to the leukemogenesis process, and (b) indicates that, in patients with inv(16)-containing AML, reexpression from the INK4b locus in the leukemia would not be predicted to occur using hypomethylating drugs. [Cancer Res 2007;67(3):992–1000]
REPORTS: Serum Protease Inhibitor Abrogation of Newcastle Disease Virus Enhancement of Cytolysis by Recombinant Tumor Necrosis Factors Alpha and Beta
Authors: P. A. Rood, R. M. Lorence, K. W. Kelley
Journal: JNCI Journal of the National Cancer Institute (1990)

Newcastle disease virus (NDV) has been used to induce regression of tumors in human cancer patients. We recently demonstrated that human malignant melanoma cells resistant to the lytic effects of tumor necrosis factor-α (TNF-α) become susceptible after treatment with NDV. We examined the effects of a serine protease inhibitor, N -1-tosylamide-2-phenylethyl-chloromethyl ketone (TPCK), on viral enhancement of TNF cytotoxicity. Virulent NDV (but neither heat-nor UV-inactivated NDV) induced a 100-fold increase in the sensitivity of murine fibroblast L929 cells to recombinant human TNF-α (rHuTNF-α), rHuTNF-β, and recombinant murine TNF-α (rMuTNF-α). TPCK, which is an inhibitor of chymotrypsin-like proteases, blocked between 42% and 93% of the cytolytic activity of rMuTNF-α, rHuTNF-α, and rHuTNF-β toward NDV-treated L929 cells. Similarly, TPCK abrogated 62% of the cytotoxicity of rMuTNF-α toward dactinomycin-treated L929 cells. In contrast, TPCK had no effect on WEHI 164 clone 13 cells, a murine fibrosarcoma cell line that is much more sensitive to the lytic effects of TNF and does not show enhanced sensitivity to TNF after treatment with either NDV or dactinomycin. These results suggest a role for a cellular protease in the mechanism by which some viruses sensitize tumor cells to the cytolytic activity of TNF. [J Natl Cancer Inst 82: 213–217, 1990]
Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials
Authors: Bonaventura Clotet, Nicholas Bellos, Jean-Michel Molina, David Cooper, Jean-Christophe Goffard, Adriano Lazzarin, Andrej Wöhrmann, Christine Katlama, Timothy Wilkin, Richard Haubrich, Calvin Cohen, Charles Farthing, Dushyantha Jayaweera, Martin Markowitz, Peter Ruane, Sabrina Spinosa-Guzman, Eric Lefebvre
Journal: The Lancet (2007)
The impact of inter-observer variation in pathological assessment of node-negative breast cancer on clinical risk assessment and patient selection for adjuvant systemic treatment
Authors: J.M. Bueno-de-Mesquita, D.S.A. Nuyten, J. Wesseling, H. van Tinteren, S.C. Linn, M.J. van de Vijver
Journal: Annals of Oncology (2009)
Multiple antibody reactivities to citrullinated antigens in sera from patients with rheumatoid arthritis: association with HLA-DRB1 alleles
Authors: O Snir, M Widhe, C von Spee, J Lindberg, L Padyukov, K Lundberg, Å Engström, P J Venables, J Lundeberg, R Holmdahl, L Klareskog, V Malmström
Journal: Annals of the Rheumatic Diseases (2008)

Autoantibodies to cyclic citrullinated peptides (anti-CCP) are present in most patients with rheumatoid arthritis (RA), and associate with HLA-DRB1 shared epitope (SE) alleles.To investigate reactivities of anti-CCP to various citrullinated proteins/peptides, which represent potential autoantigens in RA, and to examine the relationship between such antibodies, and their association with genetic variants within HLA-DRB1 SE alleles.Serum samples from 291 patients with established RA and 100 sex- and age-matched healthy subjects were included in this study. Sera were first analysed for presence of anti-CCP antibodies and further for IgG and IgA antibodies towards candidate autoantigens in both their native and citrullinated form including: fibrinogen, alpha-enolase peptide-1 and the C1-epitope of type II collagen (C1(III)). Antibody specificity was confirmed by cross-reactivity tests. HLA-DR genotyping was performed.72% of patients with RA were anti-CCP positive. Among the candidate autoantigens examined, IgG antibodies to citrullinated fibrinogen were found in 66% of patients' sera and in 41% for both citrullinated alpha-enolase peptide-1 and citrullinated C1(III). These antibodies were mainly seen in the anti-CCP-positive patient group; they were specific for their respective antigen and displayed limited cross reactivity. IgA responses were also detected, but less frequently than IgG. Anti-CCP and anti-citrullinated protein antibodies were associated with HLA-DRB1*04 rather than with HLA-DRB1*01 alleles.Antibodies directed against several citrullinated antigens are present in CCP-positive RA, with many patients displaying multireactivity. All specific reactivities were primarily associated with the HLA-DRB1*04 alleles, suggesting common pathways of anti-citrulline immunity.