tbuckley/cabot-search huggingface dataset:
A Phase I First-in-Human Pharmacokinetic and Pharmacodynamic Study of Serdemetan in Patients with Advanced Solid Tumors
Authors: Josep Tabernero, Luc Dirix, Patrick Schöffski, Andrés Cervantes, Jose Antonio Lopez-Martin, Jaume Capdevila, Ludy van Beijsterveldt, Suso Platero, Brett Hall, Zhilong Yuan, Roland Knoblauch, Sen Hong Zhuang
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Originally isolated on the basis of its ability to induce p53, serdemetan showed potent activity in various preclinical models, inducing S-phase arrest and apoptosis in TP53 wild-type and mutant tumors. This study evaluated the safety and tolerability of serdemetan, determined the pharmacokinetic and pharmacodynamic profiles, and identified a recommended phase II dose. Patients and Methods: Patients (71) with refractory solid tumors were allocated to dose-escalating cohorts (3+3 patients each) and received oral serdemetan once daily in 21-day cycles to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). Plasma was collected for pharmacokinetic analyses. Paired baseline and on-treatment skin and tumor biopsies were done; blood samples were collected for pharmacodynamic analyses, including p53 and macrophage inhibitory cytokine-1 induction. Results: The MTD of serdemetan was determined to be 350 mg once daily. During this study, grade 3 QTc prolongation was the most common DLT and nausea (66.2%) was the most frequent treatment-emergent adverse event. Serdemetan was rapidly absorbed after oral administration and exhibited dose-proportional pharmacokinetics. At steady state, mean maximum plasma concentration (Cmax) was 2,330 ng/mL and mean area under plasma concentration curve (AUC0–24h) was 43.0 μg.h/mL, with serdemetan 300 mg/d. There was a dose- and exposure-dependent p53 induction. One patient with breast cancer showed a partial response; 22 (38.6%) patients had stable disease. Conclusions: Serdemetan treatment was associated with p53 induction in both tumor and surrogate tissue pharmacodynamic studies and modest clinical activity. Although serdemetan was well tolerated with dose-proportional pharmacokinetics, exposure-related QTc liability was observed. Clin Cancer Res; 17(19); 6313–21. ©2011 AACR.
Pregnancy Complications Following Prenatal Exposure to SSRIs or Maternal Psychiatric Disorders: Results From Population-Based National Register Data
Authors: Heli Malm, Andre Sourander, Mika Gissler, David Gyllenberg, Susanna Hinkka-Yli-Salomäki, Ian W. McKeague, Miia Artama, Alan S. Brown
Journal: American Journal of Psychiatry (2015)

Objective: Using national register data, the authors examined the relationship between prenatal selective serotonin reuptake inhibitor (SSRI) treatment and pregnancy complications, accounting for psychiatric diagnoses related to SSRI use. Method: This was a population-based prospective birth cohort study using national register data. The sampling frame included 845,345 offspring, representing all singleton live births in Finland between 1996 and 2010. Pregnancies were classified as exposed to SSRIs (N=15,729), unexposed to SSRIs but with psychiatric diagnoses (N=9,652), and unexposed to medications and psychiatric diagnoses (N=31,394). Pregnancy outcomes in SSRI users were compared with those in the unexposed groups. Results: Offspring of mothers who received SSRI prescriptions during pregnancy had a lower risk for late preterm birth (odds ratio=0.84, 95% CI=0.74–0.96), for very preterm birth (odds ratio=0.52, 95% CI=0.37–0.74), and for cesarean section (odds ratio=0.70, 95% CI=0.66−0.75) compared with offspring of mothers unexposed to medications but with psychiatric disorders. In contrast, in SSRI-treated mothers, the risk was higher for offspring neonatal complications, including low Apgar score (odds ratio=1.68, 95% CI=1.34–2.12) and monitoring in a neonatal care unit (odds ratio=1.24, 95% CI=1.14–1.35). Compared with offspring of unexposed mothers, offspring of SSRI-treated mothers and mothers unexposed to medications but with psychiatric disorders were both at increased risk of many adverse pregnancy outcomes, including cesarean section and need for monitoring in a neonatal care unit. Conclusions: In a large national birth cohort, treatment of maternal psychiatric disorders with SSRIs during pregnancy was related to a lower risk of preterm birth and cesarean section but a higher risk of neonatal maladaptation. The findings provide novel evidence for a protective role of SSRIs on some deleterious reproductive outcomes, possibly by reducing maternal depressive symptoms. The divergent findings suggest that clinical decisions on SSRI use during pregnancy should be individualized, taking into account the mother’s psychiatric and reproductive history.
Cetuximab and Cisplatin for Chemotherapy-Refractory Squamous Cell Cancer of the Head and Neck
Authors: Barbara Burtness
Journal: Journal of Clinical Oncology (2005)

Squamouscellcarcinomaoftheheadandneckremains a challenging clinical problem. The majority of patients who present with stage III and IV disease will not be cured by chemoradiotherapy or surgery, and metastatic disease is increasingly common with the use of successful regimens for treatment of locoregional disease. Systemic therapies have not been curative, and median survival times have remained less than a year for patients with recurrent or metastatic disease. Head and neck cancers are rich in expression of the epidermal growth factor receptor (EGFR), which has been proposed as an important therapeutic target in these tumors. 1 Overexpression has been associated with worse prognosis. 2 Activated EGFR signals via the ras, ERK1/2, PI3K/Akt, and stat pathways and results in treatment resistance,angiogenesis,enhancedproliferation,andexpression
Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders
Authors: Joost P.H. Drenth, Stephen G. Waxman
Journal: Journal of Clinical Investigation (2007)

The voltage-gated sodium-channel type IX α subunit, known as Nav1.7 and encoded by the gene SCN9A, is located in peripheral neurons and plays an important role in action potential production in these cells. Recent genetic studies have identified Nav1.7 dysfunction in three different human pain disorders. Gain-of-function missense mutations in Nav1.7 have been shown to cause primary erythermalgia and paroxysmal extreme pain disorder, while nonsense mutations in Nav1.7 result in loss of Nav1.7 function and a condition known as channelopathy-associated insensitivity to pain, a rare disorder in which affected individuals are unable to feel physical pain. This review highlights these recent developments and discusses the critical role of Nav1.7 in pain sensation in humans.
RyR-NCX-SERCA Local Cross-Talk Ensures Pacemaker Cell Function at Rest and During the Fight-or-Flight Reflex
Authors: Anna V. Maltsev, Yael Yaniv, Michael D. Stern, Edward G. Lakatta, Victor A. Maltsev
Journal: Circulation Research (2013)

Rationale: A recent study published in Circulation Research by Gao et al used sinoatrial node (SAN)–targeted, incomplete Ncx1 knockout in mice to explore the role of the Na + /Ca 2+ exchanger (NCX) in cardiac pacemaker. The authors concluded that NCX is required for increasing sinus rates, but not for maintaining resting heart rate. This conclusion was based, in part, on numeric model simulations performed by Gao et al that reproduced their experimental results of unchanged action potentials in the knockout SAN cells. The authors, however, did not simulate the NCX current (I NCX ), that is, the subject of the study. Objective: We extended numeric examinations to simulate I NCX in their incomplete knockout SAN cells that is crucial to interpret the study results. Methods and Results: I NCX and Ca 2+ dynamics were simulated using different contemporary numeric models of SAN cells. We found that minimum diastolic Ca 2+ levels and I NCX amplitudes generated by remaining NCX molecules (only 20% of control) remained almost unchanged. Simulations using a new local Ca 2+ control model indicate that these powerful compensatory mechanisms involve complex local cross-talk of Ca 2+ cycling proteins and NCX. Specifically, lower NCX expression facilitates Ca 2+ -induced Ca 2+ release and larger local Ca 2+ releases that stabilize diastolic I NCX . Further reduction of NCX expression results in arrhythmia and halt of automaticity. Conclusions: Remaining NCX molecules in the incomplete knockout model likely produce almost the same diastolic I NCX as in wild-type cells. I NCX contribution is crucially important for both basal automaticity of SAN cells and during the fight-or-flight reflex.
Influence of Dietary Retinyl Acetate on Normal Rat Mammary Gland Development and on the Enhancement of 7,12-Dimethylbenz[&lt;italic&gt;a&lt;/italic&gt;]anthracene-Induced Rat Mammary Tumorigenesis by High Levels of Dietary Fat&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: C F Aylsworth, M E Cullum, M H Zile, C W Welsch
Journal: JNCI Journal of the National Cancer Institute (1986)

The effect of high levels of dietary fat and retinyl acetate (ROA) on 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumor development and growth was examined. Female Sprague-Dawley rats, 51-53 days of age, were treated ig with 5 mg DMBA. At 55-57 days of age, the animals were divided into the following dietary treatment groups: A) 4.5% fat [control fat (CF)]; B) CF + 1.0 mmol ROA/kg diet (CF + ROA); C) 20.0% fat [high fat (HF)]; and D) HF + ROA. HF diets significantly increased mammary tumor multiplicity, with or without ROA, but did not significantly influence mammary tumor growth. ROA treatment reduced mammary tumor multiplicity regardless of the level of dietary fat and inhibited mammary tumor growth in the presence of normal levels of dietary fat. High levels of dietary fat did not significantly influence normal mammary gland growth and development. ROA significantly decreased normal mammary gland growth and development regardless of the level of dietary fat. Blood retinoids in rats fed ROA were primarily in the form of retinyl esters, i.e., retinyl linoleate, retinyl palmitate-oleate, and retinyl stearate. Free retinol levels in blood were not significantly influenced by ROA feeding. Blood retinyl ester levels were lower in rats fed the HF + ROA diet as compared to rats fed the CF + ROA diet.
Allogeneic tumor cells expressing fusogenic membrane glycoproteins as a platform for clinical cancer immunotherapy.
Authors: Fiona Errington, Andrew Bateman, Tim Kottke, Jill Thompson, Kevin Harrington, Alison Merrick, Paul Hatfield, Peter Selby, Richard Vile, Alan Melcher
Journal: Clinical Cancer Research (2006)

Abstract PURPOSE: Fusogenic membrane glycoproteins (FMG), such as the vesicular stomatitis virus G glycoprotein (VSV-G), represent a new class of gene therapy for cancer that cause cytotoxic fusion on expression in tumor cells. In addition, FMG-mediated tumor cell death stimulates antitumor immunity, suggesting potential applications for FMG-expressing cellular vaccines. This study addresses the promise of FMG-expressing allogeneic tumor cells, which are most practical for clinical use, as a novel platform for ex vivo and in situ vaccination. EXPERIMENTAL DESIGN: Murine B16 melanoma-derived cell lines expressing autologous or allogeneic MHC class I, expressing fusogenic or nonfusogenic VSV-G, were used to vaccinate mice in vivo against a live tumor challenge. Exosome-like vesicles released by fusing allogeneic cells (syncitiosomes) and intratumoral injection of fusing vaccines were also tested as novel therapeutic strategies for their antitumor effects. RESULTS: Expression of fusogenic VSV-G enhanced the immunogenicity of an allogeneic cellular vaccine, which was more effective than a fusing autologous vaccine. Allogeneic syncitiosomes were only as effective as cellular vaccines when administered with adjuvant, demonstrating that syncitiosomes cannot account entirely for the mechanism of immune priming. Intratumoral injection of FMG-expressing allogeneic cells led to significant tumor regression using both fusogenic or nonfusogenic VSV-G. However, specific priming against tumor-associated antigenic epitopes and protection against secondary rechallenge only occurred if the initial vaccine was competent for cell fusion. CONCLUSIONS: FMG-expressing allogeneic tumor cells are a potent source of antitumor vaccines. Syncitiosomes given with adjuvant and intratumoral injection of fusing cells represent novel strategies well-suited to clinical translation.
Visceral Adiposity and the Risk of Impaired Glucose Tolerance
Authors: Tomoshige Hayashi, Edward J. Boyko, Donna L. Leonetti, Marguerite J. McNeely, Laura Newell-Morris, Steven E. Kahn, Wilfred Y. Fujimoto
Journal: Diabetes Care (2003)

OBJECTIVE—Greater visceral adiposity, higher insulin resistance, and impaired insulin secretion increase the risk of type 2 diabetes. Whether visceral adiposity increases risk of impaired glucose tolerance (IGT) independent of other adipose depots, insulin resistance, and insulin secretion is not known. RESEARCH DESIGN AND METHODS—Study subjects included 128 Japanese Americans with normal glucose tolerance at entry. Baseline variables included plasma glucose and insulin measured after an overnight fast and during a 75-g oral glucose tolerance test, fat areas by computed tomography, insulin secretion (incremental insulin response [IIR] [30 min insulin − fasting insulin]/30 min glucose), and insulin resistance index (homeostasis model assessment for insulin resistance [HOMA-IR]). RESULTS—During the 10- to 11-year follow-up period, we confirmed 57 cases of IGT. Significant predictors of IGT included intra-abdominal fat area (IAFA) (odds ratio [OR] for a 1 SD increase 3.82, 95% CI 1.63–8.94 at a fasting plasma glucose [FPG] level of 4.5 mmol/l), HOMA-IR (2.41, 1.15–5.04), IIR (0.30, 0.13–0.69 at an FPG level of 4.5 mmol/l), the interactions of IAFA by FPG (P = 0.003), and IIR by FPG (P = 0.030) after adjusting for age, sex, FPG, and BMI. The multiple-adjusted OR of IAFA increased and that of IIR decreased as FPG level decreased because of these interactions. Even after adjustment for total fat area, total subcutaneous fat area, or abdominal subcutaneous fat area, all of these associations remained a significant predictor of IGT incidence. CONCLUSIONS—Greater visceral adiposity increases the risk of IGT independent of insulin resistance, insulin secretion, and other adipose depots in Japanese Americans.
Relationship among salivary androstenedione, body composition and physical activity in young girls
Authors: A J McKune, K D DuBose
Journal: British Journal of Sports Medicine (2010)

High androgenic activity in young girls may be associated with adiposity and the development of metabolic disturbances. This study examined the relationship between salivary androstenedione, body composition and physical activity (PA) levels in young girls. Twenty-three prepubescent girls (8.4±0.9 years), 9 normal and 14 overweight, according to Centres for Disease Control and Prevention body mass index (BMI) percentile ranking, wore an ActiGraph accelerometer for 5 days. Skinfolds were measured for per cent body fat and fat free mass calculation. Saliva samples were collected three times at home over 1 day (waking, 30-min postwaking and evening). Previously published cut points estimated the minutes of moderate, moderate-to-vigorous (MVPA), vigorous and very vigorous PA. Meeting PA recommendations was defined as accumulating 60 min/day of MVPA. t Tests, correlation and regression analysis examined relationships between the variables. Only 35% of the girls met current PA recommendations. Evening androstenedione levels were significantly higher among girls who did not meet the PA recommendations. Evening androstenedione levels were negatively related to time spent performing very vigorous PA and positively related to the per cent change in androstenedione from waking to evening. There were no correlations between androstenedione and BMI or per cent body fat. Salivary androstenedione is related to PA, but not either BMI or per cent body fat in young girls. This suggests an important role for PA in determining androgenic activity independently from the proposed mechanism linking adiposity with elevated androgenic activity.
Premature ovarian failure
Authors: Deepti Goswami, Gerard S. Conway
Journal: Human Reproduction Update (2005)

Premature ovarian failure (POF) causing hypergonadotrophic hypogonadism occurs in 1% of women. In majority of cases the underlying cause is not identified. The known causes include: (a) Genetic aberrations, which could involve the X chromosome or autosomes. A large number of genes have been screened as candidates for causing POF; however, few clear causal mutations have been identified. (b) Autoimmune ovarian damage, as suggested by the observed association of POF with other autoimmune disorders. Anti-ovarian antibodies are reported in POF by several studies, but their specificity and pathogenic role are questionable. (c) Iatrogenic following surgical, radiotherapeutic or chemotherapeutic interventions as in malignancies. (d) Environmental factors like viral infections and toxins for whom no clear mechanism is known. The diagnosis is based on finding of amenorrhoea before age 40 associated with FSH levels in the menopausal range. Screening for associated autoimmune disorders and karyotyping, particularly in early onset disease, constitute part of the diagnostic work-up. There is no role of ovarian biopsy or ultrasound in making the diagnosis. Management essentially involves hormone replacement and infertility treatment, the only proven means for the latter being assisted conception with donated oocytes. Embryo cryopreservation, ovarian tissue cryopreservation and oocyte cryopreservation hold promise in cases where ovarian failure is foreseeable as in women undergoing cancer treatments.
Hypoxia Modulates EWS-FLI1 Transcriptional Signature and Enhances the Malignant Properties of Ewing's Sarcoma Cells <i>In vitro</i>
Authors: Dave N.T. Aryee, Stephan Niedan, Maximilian Kauer, Raphaela Schwentner, Idriss M. Bennani-Baiti, Jozef Ban, Karin Muehlbacher, Michael Kreppel, Robert L. Walker, Paul Meltzer, Christopher Poremba, Reinhard Kofler, Heinrich Kovar
Journal: Cancer Research (2010)

Hypoxia is an important condition in the tumor cell microenvironment and approximately 1% to 1.5% of the genome is transcriptionally responsive to hypoxia with hypoxia-inducible factor-1 (HIF-1) as a major mediator of transcriptional activation. Tumor hypoxia is associated with a more aggressive phenotype of many cancers in adults, but data on pediatric tumors are scarce. Because, by immunohistochemistry, HIF-1alpha expression was readily detectable in 18 of 28 primary Ewing's sarcoma family tumors (ESFT), a group of highly malignant bone-associated tumors in children and young adults, we studied the effect of hypoxia on ESFT cell lines in vitro. Intriguingly, we found that EWS-FLI1 protein expression, which characterizes ESFT, is upregulated by hypoxia in a HIF-1alpha-dependent manner. Hypoxia modulated the EWS-FLI1 transcriptional signature relative to normoxic conditions. Both synergistic as well as antagonistic transcriptional effects of EWS-FLI1 and of hypoxia were observed. Consistent with alterations in the expression of metastasis-related genes, hypoxia stimulated the invasiveness and soft agar colony formation of ESFT cells in vitro. Our data represent the first transcriptome analysis of hypoxic ESFT cells and identify hypoxia as an important microenvironmental factor modulating EWS-FLI1 expression and target gene activity with far-reaching consequences for the malignant properties of ESFT.
Incidence of cancer in the context of atopic dermatitis: reply from authors
Authors: A. Arana, C.E. Wentworth, C. Fernández-Vidaurre, R.G. Schlienger, E. Conde, F.M. Arellano
Journal: British Journal of Dermatology (2011)

Journal Article Incidence of cancer in the context of atopic dermatitis: reply from authors Get access A. Arana, A. Arana Risk Management Resources Pharmacovigilance Services SL, 50001 Zaragoza, Spain Search for other works by this author on: Oxford Academic Google Scholar C.E. Wentworth, C.E. Wentworth Risk Management Resources, LLC, Bridgewater, NJ, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar C. Fernández‐Vidaurre, C. Fernández‐Vidaurre Novartis Pharmaceuticals Corp., Global Clinical Epidemiology, East Hanover, NJ, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar R.G. Schlienger, R.G. Schlienger Novartis Pharma AG, Global Clinical Epidemiology, Basel, Switzerland Search for other works by this author on: Oxford Academic Google Scholar E. Conde, E. Conde Hematology Department, Hospital Marqués de Valdecilla, Santander, SpainFaculty of Medicine, Universidad de Cantabria, Santander, Spain E‐mail: arana.riskmr@gmail.com Search for other works by this author on: Oxford Academic Google Scholar F.M. Arellano F.M. Arellano Risk Management Resources Pharmacovigilance Services SL, 50001 Zaragoza, SpainRisk Management Resources, LLC, Bridgewater, NJ, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 164, Issue 4, 1 April 2011, Pages 897–898, https://doi.org/10.1111/j.1365-2133.2011.10228.x Published: 01 April 2011
Some Effects of a Cardioactive Fraction Isolated from Human Blood Plasma on the Peripheral Circulation of the Dog
Authors: Winifred G. Nayler, David Race, Jocelyn M. Price, Thomas E. Lowe
Journal: Circulation Research (1966)

Using dogs on heart-lung bypass and perfused hind-limb preparations, the effect of the relatively low molecular weight cardioactive plasma fraction on the peripheral circulation of dogs was investigated. This cardioactive plasma fraction raised the arterial blood pressure of dogs on bypass and increased the perfusion pressure in hind-limb preparations. The raised arterial pressure was found to be associated with increased blood flow through the coronary and splanchnic beds; flow through the hind limb decreased. Adrenalectomyand nephrectomy did not abolish these peripheral effects of this plasma fraction. It is concluded that the raised systemic arterial pressures recorded from intact animals following the injection of this plasma fraction may result, in part, from the effect on the peripheral circulation.