tbuckley/cabot-search huggingface dataset:
Abstract SY10-03: Cell of origin in pediatric medulloblastomas
Authors: Daisuke Kawauchi, Giles Robinson, Tamar Uziel, David W. Elisson, Richard J. Gilbertson, Martine F. Roussel
Journal: Cancer Research (2012)

Abstract Medulloblastoma is the most common malignant brain tumor in children with a median age of 3 to 7 years old. Human medulloblastomas are molecularly classified into four major subgroups including two with constitutive activation of developmental signaling pathways Sonic Hedgehog/Patched defining the SHH-subgroup and Wnt for the WNT-subgroup, subgroup 3 with amplification or overexpression of c-MYC and subgroup 4 with as yet undefined genetic anomalies. To date, all medulloblastomas regardless of their subgroup are treated with the same therapeutic regimen with different outcome. If children with WNT-subgroup tumors fair well, those with subgroup 3 medulloblastoma, the most aggressive form of the disease have a dismal prognosis. Most mouse models of medulloblastoma developed to date mimic the human SHH-subgroup. However, we recently developed two new mouse models that faithfully recapitulate the human WNT-subgroup and subgroup 3 (MYC). The SHH-subgroup and subgroup 3 medulloblastomas were derived from cerebellar granule progenitors in the external granule layer which sustain mutations in the SHH pathway associated with MYCN overexpression, or C-MYC amplification, respectively. In contrast, the WNT-subgroup medulloblastoma with mutations in β-Catenin originate from the lower rhombic lip, the germinal neuroepithelium surrounding the floor of the 4th ventricle, suggesting that each subgroup may originate from specific neuronal precursors within the developing cerebellum. Mouse subgroup 3 medulloblastomas, but not SHH- or WNT-subgroup tumors can be passaged indefinitely as neurospheres that express markers characterizing stem cells, including Lgr5, Oct4, Nanog, and Sox2 and induce secondary medulloblastomas with similar characteristics as the primary tumors, after orthotopic transplant into the cortices of recipient mice. These novel medulloblastoma mouse models should significantly advance our efforts to develop new therapeutic modalities for this deadly childhood cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY10-03. doi:1538-7445.AM2012-SY10-03
Abstract 3365: Population pharmacokinetics of oxaliplatin: An analysis across human development in infants, children and adults.
Authors: Mina Nikanjam, Clinton F. Stewart, Chris H. Takimoto, Timothy W. Synold, Edmund V. Capparelli
Journal: Cancer Research (2013)

Abstract Introduction: Oxaliplatin has been studied in both adult and pediatric clinical trials as therapy for a variety of solid and hematologic malignancies, but no comprehensive pharmacokinetic analysis has been conducted to define the impact of age on oxaliplatin disposition. We combined platinum ultrafiltrate concentration data from 4 separate studies to characterize oxaliplatin pharmacokinetics across a wide range of ages and renal function. Methods: Oxaliplatin pharmacokinetic data from Phase I and II clinical trials included 2 pediatric studies (median age 11.2 yr, range 1.3 - 22.7) and 2 adult NCI organ dysfunction studies (median age 63 yr, range 28 - 86). Oxaliplatin was given as a 2 hour infusion; the majority of subjects received 130 mg/m2 (range 60 - 160 mg/m2). Plasma samples were obtained 2- 504 hours after dosing with the pharmacokinetic analysis performed using platinum ultrafiltrate concentrations (LLOQ 1-10 ng/mL). In total 161 subjects (1416 samples) were analyzed using nonlinear mixed effects modeling (NONMEM v. VI). Results: Oxaliplatin concentration data required a four compartment model to characterize later samples. Serum creatinine (SCR) and age were independent predictors of clearance (CL) in the univariate screen, but age was not significant in the multivariate screen. CL increased with allometric weight, but decreased with SCR. Typical values were: 24.6 L/kg (volume of distribution) and 0.526 x (SCR/0.9)0.926 L/h/kg0.75 (CL, variability 63.8%). The final model was used to simulate a dose of 130 mg/m2 in 1000 subjects with the median (IQR) exposure (AUC), CL, and SCR as follows: SCR (mg/dL) CL (L/hr/m2) AUC (mcg*hr/mL) Age 1 yr 0.7 (0.6–0.8) 7.4 (4.6–11.6) 17.5 (11.2–28.3) Age 5 yr 0.7 (0.6–0.8) 7.9 (4.9–11.7) 16.4 (11.1–26.3) Age 50 yr 1.0 (0.9–1.2) 6.4 (4.3–10.3) 20.3 (12.6–30.4) Age 50 yr (renal dysfunction) 2.2 (1.8–2.6) 3.2 (2.0–4.9) 40.5 (26.3–65.9) Conclusions: This combined analysis suggests that earlier models limited to 2 or 3 compartments may not characterize the true terminal phase of oxaliplatin. Differences in age were entirely accounted for by weight and renal function. Standard BSA based dosing results in similar AUC and CL values between pediatric and adult patients with adequate renal function. Citation Format: Mina Nikanjam, Clinton F. Stewart, Chris H. Takimoto, Timothy W. Synold, Edmund V. Capparelli. Population pharmacokinetics of oxaliplatin: An analysis across human development in infants, children and adults. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3365. doi:10.1158/1538-7445.AM2013-3365
Abstract 3907: Emergent properties of EWS/FLI regulation via GGAA-microsatellites in Ewing's sarcoma
Authors: Kunal Gangwal, Camille A. Enriquez, Devin Close, Christopher P. Hill, Stephen L. Lessnick
Journal: Cancer Research (2010)

Abstract ETS proteins are a family of transcription factors that play important roles in the development of cancer. The Ewing's sarcoma EWS/ETS fusion oncoproteins control a number of cancer-relevant phenotypes in that disease. We recently demonstrated that EWS/FLI, the most common EWS/ETS fusion in Ewing's sarcoma, regulates a portion of its target genes, including the critical target NR0B1, via GGAA-containing microsatellites in their promoters. Given the unusual nature of microsatellites as EWS/FLI response elements, we sought to elucidate the mechanism of EWS/FLI activity at these sites. In addition to EWS/FLI, we found that other Ewing's sarcoma associated EWS/ETS fusions are capable of mediating gene regulation via the NR0B1 microsatellite. Furthermore, regulation via the GGAA microsatellite was specific to Ewing's sarcoma fusion proteins as two other ETS family members, ETS1 and ELF1, could not cause transcriptional activation, highlighting a neomorphic function of the Ewing's sarcoma fusion proteins. The stoichiometry of this interaction is 2 protein molecules for each DNA molecule, suggesting that EWS/FLI binds these elements as a homodimer. The isolated FLI ETS domain bound microsatellite sequences in a nearly identical fashion to full-length EWS/FLI, thus indicating that residues required for homodimeric binding are localized to the ETS domain. These data suggest a new paradigm for ETS family member binding to DNA at cancer-relevant genetic loci, and highlight emergent properties of EWS/FLI that are required for the development of Ewing's sarcoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3907.
Abstract 4978: <i>FOXP3</i> up-regulates <i>p21</i> expression in breast cancer: Evidence for tumor suppressor
Authors: Runhua Liu, Lizhong Wang, Hiroto Katoh, Pan Zheng, Yang Liu
Journal: Cancer Research (2010)

Abstract FOXP3 is the first X-linked breast cancer suppressor gene that works at least in part by repression of oncogenes, including HER-2 and SKP2. Since FOXP3 is also known as a transcription activator, we investigated the possibility that FOXP3 may induce expression of tumor suppressor genes. p21 loss has been implicated in conferring oncogenic activity to known tumor suppressor gene KLF4 and cancer drug tamoxifen. Regulators of p21, therefore, play critical roles in tumorigenesis. Here, we report that X-linked tumor suppressor FOXP3 is essential for p21 expression in normal epithelia and that lack of FOXP3 is associated with p21 down-regulation in breast cancer samples. Among 62 primary breast cancer samples tested, a strong association between FOXP3 down-regulation and lack of p21 was observed. Moreover, siRNA silencing of FOXP3 in primary human mammary epithelial cells leads to a dramatic reduction in expression of p21, which demonstrates an important role of FOXP3 in maintaining expression of p21 in normal breast epithelial cells. In breast cancer cell line MCF-7, an inducible expression of FOXP3 is associated with induction of p21. Since silencing p21 reduced the efficacy of FOXP3-mediated growth inhibition, the induced expression of p21 contributes to growth inhibition by FOXP3. A specific FOXP3 binding site in the intron 1, which is associated with acetylated histone H3, is essential for p21 induction by FOXP3. FOXP3 specifically inhibited binding of histone deacetylase 2 (HDAC2) and HDAC4 to the site and increased local histone H3 acetylation. Short hairpin RNA silencing of either HDAC2 or HDAC4 is sufficient to induce p21 expression. Our data provides a novel mechanism for transcription activation by FOXP3 and a genetic mechanism for lack of p21 in a large proportion of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4978.
THU0325 Lack of Relation between Inflammation on Joint Level and Fibromyalgia Symptoms in Patients with Rheumatoid Arthritis: Table 1
Authors: S. Chrysidis, P.R. Lage-Hansen, A. Colic, J.K. Sørensen, L. Ejstrup
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Fibromyalgia (FM) exists in a substantial number of patients with rheumatoid arthritis (RA) (approx. 15%), who have higher disease activity as measured by DAS-28, than RA patients without concomitant FM. It is important to understand if there is an association between active inflammation on joint level and FM symptoms in RA patients <h3>Objectives</h3> In this study, we examined the relation between joint inflammation and FM symptoms in RA patients. We hypothesized that there is no correlation between the severity of inflammation on joint level and FM symptoms. <h3>Methods</h3> In a period of 8 months, RA patients (US-RA group) who were candidates to biological treatment underwent ultrasound (US) examination (Hitachi Preirus,14 or 18 MHz linear transducer) before initiation of biological treatment. The patients underwent screening for fibromyalgia (FM) using The Modified 2010 American College of Rheumatology (ACR) Diagnostic Criteria. Two experienced ultrasonographers (SC, AC) blinded to the DAS-28 and FM results performed the UL examination, while experienced nurses, blinded on US and FM results performed the DAS28 calculation. In a study made at the same period of time in our department we found that 13 RA patients in established biological treatment were diagnosed as having concomitant FM (RAF group). These patients were in a stabile treatment during the examination time and there was calculate DAS-28 in the same way as above. The comparisons between US-RA and RAF groups were performed by unpaired t-test after confirming normal distribution of data. <h3>Results</h3> We included 13 patients in the US-RA group. They had at least two joints with high inflammation (Grey scale synovitis grade II and Colour Doppler grade II as minimum). They were screened for FM and only one of these patients fulfilled the Modified 2010 ACR diagnostic criteria. Three months later all patients were in DAS remission/low disease activity, except the patient with concomitant FM, who still had moderate high DAS because of many tender joints and high VAS-GH. We also compared the US-RA group with RAF group and there was no significant difference in age, gender, disease duration &amp; seropositivity. The rest of comparisons between the two groups are shown in Table 1. <h3>Conclusions</h3> We did not find evidence that RA patients with high inflammation on joint level have higher rates of FM. Biological naïve RA patients (US-RA group) with high level of joints inflammation as confirmed by US had less severe subjective symptoms (VAS &amp; HAQ) compared to RAF patients in a stabile biological treatment phase and without swollen joins. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5237
The perils of a science of intentional change
Authors: Muhammad Ali Khalidi
Journal: Behavioral and Brain Sciences (2014)

Abstract The attempt to construct an applied science of social change raises certain concerns, both theoretical and ethical. The theoretical concerns relate to the feasibility of predicting human behavior with sufficient reliability to ground a science that aspires to the management of social processes. The ethical concerns relate to the moral hazards involved in the modification of human social arrangements, given the unreliability of predicting human action.
Idiopathic Aqueductal Stenosis
Authors: Santiago Abbati
Journal: New England Journal of Medicine (2012)

A 21-year-old woman presented with somnolence and confusion. She reported having progressively worsening headaches, nausea, and vomiting over the previous 5 months. Funduscopic examination showed bilateral papilledema as a clinical sign of intracranial hypertension. Computed tomography (Panel A) and magnetic resonance imaging (MRI) showed supratentorial hydrocephalus due to aqueductal stenosis (Panel B, arrow). Sagittal cine-phase MRI with the administration of contrast material showed a lack of flow-signal intensity at the aqueduct level (Panel C, asterisk). The patient received a diagnosis of idiopathic aqueductal stenosis, the most common form of obstructive hydrocephalus in adults. There was no evidence of a secondary . . .
Cancer Prevention: Out of the Shadows and Into the Cell
Authors: K. Smigel
Journal: JNCI Journal of the National Cancer Institute (1991)

Journal Article Cancer Prevention: Out of the Shadows and Into the Cell Get access Kara Smigel Kara Smigel Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 83, Issue 3, 6 February 1991, Pages 161–163, https://doi.org/10.1093/jnci/83.3.161 Published: 06 February 1991
Abstract 1859: Targeting APE-1/Ref-1 activity for prevention of non-melanoma skin cancer
Authors: Erik R. Olson, Chris C. Evans, Laurence S. Cooke, Daruka Mahadevan, G. Tim Bowden
Journal: Cancer Research (2011)

Abstract Apurinic/apyrimidinic endonuclease-1/Redox Factor-1 (APE-1) is a dual function protein and novel target for chemoprevention of ultraviolet (UV) light-induced skin carcinogenesis. Each of the primary functions of APE-1, base excision repair of DNA damaged by oxidation and transcription factor reduction after exposure to an oxidizing stimulus like UV, is performed through the activity of a unique functional domain and plays a potential role in skin cancer promotion and progression. Our hypothesis was that APE-1 activity would correlate with survival after UV irradiation due to enhanced AP-1 activity and DNA repair. Preliminary experiments with HaCaT keratinocytes, an initiated cell line with characteristic UV-signature hotspot mutations in p53, using APE-1 siRNA demonstrated that downregulation of APE-1 increased cell sensitivity to UV-induced apoptosis. We then PCR amplified APE-1 from reverse transcribed HaCaT cell RNA and cloned it into an EGFP-tagged expression vector to generate two stable APE-1 overexpressing HaCaT cell lines, HGA9 (high expressing) and HGA10 (low expressing) cells. As expected, HGA9 and HGA10 cells were less sensitive than HaCaT cells to UV-induced apoptosis by 49.6 and 43.6%, respectively. Collectively, these data indicate that APE-1 activity does in fact play a significant role in the cellular response to UV and suggest that inhibiting APE-1 activity could be an effective means of eliminating initiated cells from the skin and preventing tumor development and growth. To further evaluate APE-1 as a therapeutic target, a library of molecules was screened for their ability to dock within one of two known binding pockets on the surface of APE-1 using an in silico docking algorithm. The first pocket screened lies within the AP endonuclease domain of APE-1. Initially, five individual molecules were chosen because they were predicted to bind APE-1 better than resveratrol, a known inhibitor that has been shown to interact with APE-1 directly. These molecules are predicted to have a higher specificity for APE-1 than resveratrol and have been assessed for their ability to inhibit DNA repair in vitro using recombinant human APE-1. Novel molecules that inhibit APE-1 activity could prove valuable in preventing UV-induced skin carcinogenesis by promoting the death of initiated keratinocytes that would otherwise undergo clonal expansion and progress to skin tumors. This work was supported by NIH grants: 5P01CA027502 and 5P30CA023074 and by a generous gift from Alliance Beverage Distributing Company. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1859. doi:10.1158/1538-7445.AM2011-1859
Mediators of Ca 2+ -Dependent Secretion
Authors: Archana Chaudhry, Ronald P. Rubin
Journal: Environmental Health Perspectives (1990)

Ca", an obligatory mediator of the secretory process, acts in concert with other second messen- gers that further amplify or inhibit the secretory response.In this overview, we will consider the relative roles of diacylglycerol (DAG), arachidonic acid, and cyclic AMP (cAMP) in modulating Ca2,-dependent secretion in nonexcitable cells.DAG, a product of phospholipase C (PLC)-catalyzed breakdown of phosphoinositides, stimulates protein kinase C. Ca2" ionophores and phorbol esters (or DAG analogues) elicit a synergistic secretory response in the exocrine pancreas and parotid gland.These findings suggest that the complete activation of secretion requires stimula- tion of both Ca2+-dependent and protein kinase C-dependent pathways.Hydrolysis of phospholipids can also lead to the liberation of arachidonic acid in secretory cells.Endogenously generated arachidonic acid inhibits polyphosphoinositide synthesis in exocrine pancreas, leading to inhibition of agonist-induced IP3 formation, Ca2+-mobilization and amylase secretion.By con- trast, arachidonic acid and its metabolites stimulate PLC in the rabbit peritoneal neutrophil, causing Ca2+-mobilization and lysosomal enzyme secretion.Arachidonic acid can thus serve as a positive or negative feedback regulator of secretion induced by Ca21-mobilizing agonists.Finally, in the parotid gland, stimulation of amylase secretion by norepinephrine, the physiological mediator, which stimulates both the a and P adrenoceptors, requires the interaction of both Ca + and cAMP pathways to produce a full secretory response.These studies, taken together, indicate that phosphoinositide and cAMP-dependent pathways play coordinate roles in signal transduction, leading to the Ca2+-mediated secretion.
Clinical Pharmacology of Oral and Iv N-Methylformamide: A Pharmacologic Basis for Lack of Clinical Antineoplastic Activity
Authors: E. K. Rowinsky, D. A. Noe, D. W. Orr, L. B. Grochow, D. S. Ettinger, R. C. Donehower
Journal: JNCI Journal of the National Cancer Institute (1988)

N-Methylformamide (NMF) has been an agent of considerable interest to oncologists because of its broad spectrum of preclinical antitumor activity, tumor-differentiating abilities, and radiosensitizing and chemosensitizing properties. In this report, the pharmacokinetics of NMF are described, based on data from two phase I studies exploring both iv and oral routes of administration. Mean peak NMF plasma concentrations at recommended phase II doses were 0.46 mmol/L for NMF administered orally, 600 mg/m2 three times/week × 4 weeks every 6 weeks, and 2.78 mmol/L for NMF administered as a weekly iv bolus at 2, 000 mg/m2 × 3 weeks every 4 weeks. These NMF concentrations were significantly lower than the concentrations that have been demonstrated to induce antineoplastic and relevant biologic effects in preclinical studies. Plasma disappearance curves were biphasic in the majority of patients; however, 25% of the curves were best fit by a monoexponential kinetic model. Mean alpha half-life and beta half-life values (± SE) were 10 ± 2 and 732 ± 93 min, respectively. Volumes of distribution for the theoretical central compartment (Vc) and at steady-state (Vss) were 13.8 ± 1.1 L/m2 and 18.7 ± 1.1 L/m2, respectively. The mean plasma clearance of NMF was 19.1 ± 2.1 mL/min per square meter, and the relative contributions to parent compound disposition by respiratory and renal routes were insignificant. No metabolites were identified. Gastrointestinal absorption of oral NMF was rapid and nearly complete; oral bioavailability was calculated to be 0.87. Pharmacodynamic associations were observed between the magnitude of the area under the plasma disappearance curves and hepatotoxicity, the dose-limiting toxic effect of iv NMF, and the symptom complex of nausea, vomiting, and malaise, which precluded dose escalation of oral NMF. [J Natl Cancer Inst 1988; 80: 671–678]
Association between Maternal Diabetes and the Respiratory-Distress Syndrome in the Newborn
Authors: Marie F. Robert, Raymond K. Neff, John P. Hubbell, H. William Taeusch, Mary Ellen Avery
Journal: New England Journal of Medicine (1976)

Perinatal data on 805 infants of diabetic mothers and 10,152 infants of nondiabetic mothers were examined for a relation between maternal diabetes and respiratory-distress syndrome of the newborn. The syndrome occurred in 23.4 per cent of the diabetic vs. 1.3 per cent of the nondiabetic group. The risk of the syndrome in an infant of a diabetic mother was 23.7 times greater than that for an infant of a nondiabetic mother (P less than 0.00001). Further analysis to control for features associated with diabetes but also in themselves risk factors, such as gestational age and route of delivery, showed that respiratory-distress syndrome in infants of diabetic mothers was 5.6 times as likely to develop as in infants of nondiabetic mothers (P less than 0.00001). Thus, maternal diabetes mellitus per se predisposes to newborn respiratory-distress syndrome.