tbuckley/cabot-search huggingface dataset:
Pharmacokinetics of oxiracetam and its degraded substance (HOPAA) after oral and intravenous administration in rats
Authors: Xinhuan Wan, Xiaohong Liu, Zheng Liu, Panqin Ma, Feitong Zhang, Xiangrong Zhang, Jin Sun
Journal: Asian Journal of Pharmaceutical Sciences (2014)

The pharmacokinetics of oxiracetam and its degraded substance (4-hydroxy-2-oxo-1-pyrrolidine acetic acid, HOPAA) after oral and intravenous administration in rats were studied using an established UPLC-MS/MS method. Three groups of rats after an overnight fasted received 10 g/kg (n = 6) oxiracetam suspensions orally, and 2 g/kg (n = 6) normal or degraded oxiracetam injections intravenously via a caudal tail vein, respectively. Before the pharmacokinetic experiment, a simple safety evaluation test was conducted on the degraded oxiracetam injections containing 16.16% HOPAA in mice. There was no mortality by a single intravenous dose of 2 g/kg of degraded oxiracetam injections within two weeks, demonstrating that HOPAA was non-toxic in mice. Following intravenous administration of the normal injections, the plasma concentration-time curves of oxiracetam and HOPAA both showed a rapid elimination phase. The values of t1/2 were 3.1 ± 1.5 h for oxiracetam and 0.8 ± 0.2 h for HOPAA, and the mean residence times (MRT) were 1.2 ± 0.1 h and 0.8 ± 0.1 h, respectively. Oxiracetam and HOPAA after intravenous administration of the degraded oxiracetam injections presented elimination patterns similar to those observed in the normal injections. Oral pharmacokinetic results showed that the Tmax was less than 1.5 h for the two analytes, and both had a longer t1/2 and MRT than those of intravenous administration. Contents of HOPAA in three groups were calculated based on AUC0–t values of the two analytes. The quantitative change of HOPAA in vivo was also evaluated by comparing the plasma concentrations of HOPAA and oxiracetam at the same time for every group. Additionally, the values of absolute bioavailability of oxiracetam were about 8.0% and 7.4% calculated by the normal or degraded oxiracetam injections, which were far less than the value of 75% reported in literature, indicating the necessity of further study.
Obstructive jaundice with fever and eosinophilia
Authors: K. Inoue, H. Kanemasa, K. Inoue, M. Matsumoto, Y. Kajita, S. Mitsufuji, K. Kataoka, T. Okanoue, M. Yamada, R. Uchikawa, T. Tegoshi, N. Arizono
Journal: Gut (2007)

A 78-year-old man was admitted to our hospital with epigastric pain, fever and nausea. Cough, generalised pruritus and eosinophilia had persisted for 5 months before his admission. His temperature was 37.9°C. On examination, …
Best Practices in Cancer Nanotechnology: Perspective from NCI Nanotechnology Alliance
Authors: William C. Zamboni, Vladimir Torchilin, Anil K. Patri, Jeff Hrkach, Stephen Stern, Robert Lee, Andre Nel, Nicholas J. Panaro, Piotr Grodzinski
Journal: Clinical Cancer Research (2012)

Historically, treatment of patients with cancer using chemotherapeutic agents has been associated with debilitating and systemic toxicities, poor bioavailability, and unfavorable pharmacokinetics. Nanotechnology-based drug delivery systems, on the other hand, can specifically target cancer cells while avoiding their healthy neighbors, avoid rapid clearance from the body, and be administered without toxic solvents. They hold immense potential in addressing all of these issues, which has hampered further development of chemotherapeutics. Furthermore, such drug delivery systems will lead to cancer therapeutic modalities that are not only less toxic to the patient but also significantly more efficacious. In addition to established therapeutic modes of action, nanomaterials are opening up entirely new modalities of cancer therapy, such as photodynamic and hyperthermia treatments. Furthermore, nanoparticle carriers are also capable of addressing several drug delivery problems that could not be effectively solved in the past and include overcoming formulation issues, multidrug-resistance phenomenon, and penetrating cellular barriers that may limit device accessibility to intended targets, such as the blood-brain barrier. The challenges in optimizing design of nanoparticles tailored to specific tumor indications still remain; however, it is clear that nanoscale devices carry a significant promise toward new ways of diagnosing and treating cancer. This review focuses on future prospects of using nanotechnology in cancer applications and discusses practices and methodologies used in the development and translation of nanotechnology-based therapeutics.
Energy homeostasis targets chromosomal reconfiguration of the human GH1 locus
Authors: Hana Vakili, Yan Jin, Peter A. Cattini
Journal: Journal of Clinical Investigation (2014)

Levels of pituitary growth hormone (GH), a metabolic homeostatic factor with strong lipolytic activity, are decreased in obese individuals. GH declines prior to the onset of weight gain in response to excess caloric intake and hyperinsulinemia; however, the mechanism by which GH is reduced is not clear. We used transgenic mice expressing the human GH (hGH) gene, GH1, to assess the effect of high caloric intake on expression as well as the local chromosome structure of the intact GH1 locus. Animals exposed to 3 days of high caloric intake exhibited hyperinsulinemia without hyperglycemia and a decrease in both hGH synthesis and secretion, but no difference in endogenous production of murine GH. Efficient GH1 expression requires a long-range intrachromosomal interaction between remote enhancer sequences and the proximal promoter region through "looping" of intervening chromatin. High caloric intake disrupted this interaction and decreased both histone H3/H4 hyperacetylation and RNA polymerase II occupancy at the GH1 promoter. Incorporation of physical activity muted the effects of excess caloric intake on insulin levels, GH1 promoter hyperacetylation, chromosomal architecture, and expression. These results indicate that energy homeostasis alters postnatal hGH synthesis through dynamic changes in the 3-dimensional chromatin structure of the GH1 locus, including structures required for cell type specificity during development.
Identifying Potential Indicators of the Quality of End-of-Life Cancer Care From Administrative Data
Authors: Craig C. Earle, Elyse R. Park, Bonnie Lai, Jane C. Weeks, John Z. Ayanian, Susan Block
Journal: Journal of Clinical Oncology (2003)

To explore potential indicators of the quality of end-of-life services for cancer patients that could be monitored using existing administrative data.Quality indicators were identified and assessed by literature review for proposed indicators, focus groups with cancer patients and family members to assess candidate indicators and generate new ideas, and an expert panel ranking the meaningfulness and importance of each potential indicator using a modified Delphi approach.There were three major concepts of poor quality of end-of-life cancer care that could be examined using currently-available administrative data (such as Medicare claims): institution of new anticancer therapies or continuation of ongoing treatments very near death; a high number of emergency room visits, inpatient hospital admissions, or intensive care unit days near the end of life; and a high proportion of patients never enrolled in hospice, only admitted in the last few days of life, or dying in an acute-care setting. Concepts such as access to psychosocial and other multidisciplinary services and pain and symptom control are important and may eventually be feasible, but they cannot currently be applied in most data systems. Indicators based on limiting the use of treatments with low probability of benefit or indicators based on economic efficiency were not acceptable to patients, family members, or physicians.Several promising claims-based quality indicators were identified that, if found to be valid and reliable within data systems, could be useful in identifying health-care systems in need of improving end-of-life services.
Titanium and gold nanoparticles in asthma: the bad and the ugly
Authors: S. Lanone, J. Boczkowski
Journal: European Respiratory Journal (2011)

Engineered nanomaterials (ENMs) are defined as having at least one dimension ≤100 nm 1. When ENMs have three dimensions ≤100 nm they are called nanoparticles (NPs). ENMs have attracted a great deal of attention recently because their many technologically interesting properties have led to technological growth with ensuing economic rewards 2. Technologies involving ENMs are envisaged to become the cornerstone for a number of industrial sectors, such as micro-electronics, materials, paper, textiles, energy, cosmetics and medical devices, all capable of incorporating some nanoscale-enabled properties into their products 2. By 2015, the annual profit from ENM-based products is estimated to be US$1.1–2.5 trillion 3. Today, ENMs can be found in more than 1,000 consumer products 4. By 2015, 2 million workers will be needed to support nanotechnology industries worldwide 5. However, some of the properties of ENMs that are unique and beneficial for technological applications may also endanger human health, inducing cyto- and genotoxic effects, inflammation and even cancer 6–12. Inflammatory effects are particularly important 13–15. Free radical activity or oxidative capacity of particulate matter might be essential for provoking these inflammatory responses.

The physico-chemical features of ENMs that account for their deleterious health effects include a large ratio of surface area to mass and associated increased surface reactivity, altered physico-chemical properties, such as changes in melting point, solubility or electrical conductivity, or changes, for example, in the crystalline structure of the materials 16–20. Therefore, detailed evaluation of these characteristics is critical for the understanding of the mechanisms by which ENMs elicit biological responses.

The respiratory system is a critical route of exposure to aerosolised ENM, by accident or by occupational exposure. A rapidly increasing number of studies have evaluated the respiratory effects …
<i>PIK3CA</i> Mutations Predict Local Recurrences in Rectal Cancer Patients
Authors: Youji He, Laura J. Van't Veer, Izabela Mikolajewska-Hanclich, Marie-Louise F. van Velthuysen, Eliane C.M. Zeestraten, Iris D. Nagtegaal, Cornelis J.H. van de Velde, Corrie A.M. Marijnen
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Identifying rectal cancer patients at risk for local recurrence would allow for refinement in the selection of patients who would benefit from preoperative radiotherapy. PIK3CA, KRAS, and BRAF mutations are commonly found in colon cancers, but their prevalence has not been clearly assessed in rectal cancer. In this study, we aim to determine the mutation frequencies of PIK3CA, KRAS, and BRAF and to investigate whether a mutation may be used as a prognostic parameter in rectal cancer patients. Experimental Design: We evaluated DNA mutations in PIK3CA, KRAS, and BRAF in 240 stage I to III rectal tumors obtained from nonirradiated patients from the Dutch Total Mesorectal Excision trial. Results: PIK3CA, KRAS, and BRAF mutations were identified in 19 (7.9), 81 (33.9), and 5 (2.1) rectal cancers. Patients with PIK3CA mutations developed more local recurrences (5-year risks, 27.8 versus 9.4; P = 0.006) and tended to develop these recurrences more rapidly after surgery (median local recurrence-free interval since surgery: 7.9 versus 19.6 months; P = 0.07) than patients without PIK3CA mutations. In multivariate analysis, PIK3CA mutations remained as an independent predictor for the development of local recurrences (hazard ratio, 3.4; 95 confidence interval, 1.2-9.2; P = 0.017), next to tumor-node-metastasis stage. Conclusion: PIK3CA mutations can be used as a biomarker in identifying rectal cancer patients with an increased risk for local recurrences. Currently, our findings suggest that prospective evaluation of PIK3CA mutation status could reduce overtreatment by preoperative radiotherapy for the low-risk patients who might otherwise only experience the side effects. (Clin Cancer Res 2009;15(22):695662)
In Vivo Imaging of Tumor-Propagating Cells, Regional Tumor Heterogeneity, and Dynamic Cell Movements in Embryonal Rhabdomyosarcoma
Authors: Myron S. Ignatius, Eleanor Chen, Natalie M. Elpek, Adam Z. Fuller, Inês M. Tenente, Ryan Clagg, Sali Liu, Jessica S. Blackburn, Corinne M. Linardic, Andrew E. Rosenberg, Petur G. Nielsen, Thorsten R. Mempel, David M. Langenau
Journal: Cancer Cell (2012)
Nutrition and Chronic Renal Failure in Rats
Authors: CHRISTIANE L. MEIRELES, S. RUSS PRICE, ALINE M. L. PEREIRA, JOA[Combining Tilde]O T. A. CARVALHAES, WILLIAM E. MITCH
Journal: Journal of the American Society of Nephrology (1999)

Abstract. In chronic uremia (CRF), malnutrition is an important determinant of morbidity in adults and impaired growth in children. Causes of malnutrition include anorexia and abnormal protein and amino acid metabolism. To determine how different levels of dietary protein and CRF interact to influence growth and nutritional status, CRF and sham-operated, pair-fed control rats were fed isocaloric diets containing 8, 17, or 30% protein for 21 d to mimic dietary regimens recommended for CRF patients: the minimum daily requirement; the recommended daily allowance; or an excess of dietary protein. Serum creatinine did not differ between groups of CRF rats but blood urea nitrogen was lowest in CRF rats fed 8% protein (P < 0.001). CRF rats eating 30% protein gained less weight and length compared to their controls or CRF rats fed 8 or 17% protein (P < 0.05); they also had acidemia. CRF rats fed 8% protein had the highest efficiency of utilization of protein for growth, while 17% protein promoted the highest efficiency of utilization of food and calories for growth. Notably, CRF rats eating 30% protein had the lowest protein efficiency; their calorie intake was also the lowest because of anorexia. Plasma branched-chain amino acids were progressively higher in control rats eating 8, 17, or 30% protein. CRF rats fed 8 or 17% protein had lower branched-chain amino acid concentrations compared with CRF rats fed 30% protein. In CRF, it is concluded that excessive dietary protein impairs growth but a low-protein diet does not impair nutritional responses and permits utilization of protein for growth if calories are sufficient.
Receipt of Psychosocial Care Among Cancer Survivors in the United States
Authors: Laura P. Forsythe, Erin E. Kent, Kathryn E. Weaver, Natasha Buchanan, Nikki A. Hawkins, Juan L. Rodriguez, A. Blythe Ryerson, Julia H. Rowland
Journal: Journal of Clinical Oncology (2013)

Given the importance of psychosocial care for cancer survivors, this study used population-based data to characterize survivors who reported a discussion with health care provider(s) about the psychosocial effects of cancer and who reported using professional counseling or support groups (PCSG) and tested associations between receipt of psychosocial care and satisfaction with care.
Phase I Dose Escalation and Pharmacokinetic Study of BI 2536, a Novel Polo-Like Kinase 1 Inhibitor, in Patients With Advanced Solid Tumors
Authors: Klaus Mross, Annette Frost, Simone Steinbild, Susanne Hedbom, Jochen Rentschler, Rolf Kaiser, Nicolas Rouyrre, Dirk Trommeshauser, Cornelia E. Hoesl, Gerd Munzert
Journal: Journal of Clinical Oncology (2008)

BI 2536 is a novel, potent, and highly specific inhibitor of polo-like kinase 1 (Plk1), which has an essential role in the regulation of mitotic progression. The aim of this trial was to identify the maximum tolerated dose (MTD) of BI 2536 and to determine the safety, pharmacokinetics, and antitumor activity in patients who had advanced solid tumors.This phase I trial followed an open label, toxicity-guided, dose-titration design. Single doses of BI 2536 (25 to 250 mg) were administered as a 1-hour intravenous infusion; patients who experienced clinical benefit were eligible for additional treatment courses. Safety and pharmacokinetics were investigated. Tumor response was evaluated according to Response Evaluation Criteria in Solid Tumors Group guidelines.The MTD was defined at 200 mg in a total of 40 patients entered; reversible neutropenia constituted the dose-limiting toxicity (DLT) and the most frequent adverse event at the MTD (grade 3 to 4; 56%). Nausea (52%), fatigue (52%), and anorexia (44%) also were common and were mostly of mild to moderate intensity (Common Terminology Criteria of Adverse Events <or= grade 2). One patient experienced a transient partial response. At doses equal to or greater than the MTD, 23% of patients experienced disease stabilization for 3 or more months. Dose-proportional increases in the maximum plasma concentration and total exposure were observed. BI 2536 showed a high total clearance and high distribution into tissue.The MTD of BI 2536 when administered as a single-dose, 1-hour infusion was 200 mg; BI 2536 was well tolerated and showed a favorable pharmacokinetic profile. Antitumor activity of BI 2536 was observed.
Thyroid Nodules in the Population Living Around Chernobyl
Authors: Fred A. Mettler
Journal: JAMA (1992)

<h3>Objective.</h3> —To determine the baseline incidence, prevalence, and characteristics of thyroid nodules in the population living around the Chernobyl nuclear power plant and to compare the findings with unexposed populations. <h3>Design.</h3> —Prevalence study. Population samples from seven highly contaminated villages were compared with six nearby control villages of the same size and type. The data were obtained as part of the International Chernobyl Project conducted in 1990. <h3>Setting.</h3> —The study was conducted 4.5 years after the Chernobyl reactor accident that released large quantities of radionuclides, including radioiodine. <h3>Patients or Other Participants.</h3> —Population samples of approximately 100 persons residing in both highly contaminated villages and control villages since the accident were compared. Individuals were selected on the basis of birth date as being 5, 10, 40, or 60 years old at the time of the study. All persons selected underwent a thyroid examination. <h3>Interventions.</h3> —None. <h3>Main Outcome Measures.</h3> —Two main outcome measures were used, both for thyroid nodularity: clinical palpation and high-resolution ultrasonography. <h3>Results.</h3> —There was no significant difference in thyroid nodularity between the study groups. Nodules were palpated in 0.7% of children and 2.9% of adults. Discrete nodules were found by ultrasonography in 0.5% of children and 14.9% of adults. Multinodular goiter was found in 3% of adults. Nodules were more common in females. <h3>Conclusions.</h3> —Four and a half years after the Chernobyl accident, the incidence, prevalence, and characteristics of thyroid nodules were the same in population samples from both highly contaminated and control settlements and similar to results reported for unexposed populations in other countries. (<i>JAMA</i>. 1992;268:616-619)
Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer.
Authors: G Kemp, P Rose, J Lurain, M Berman, A Manetta, B Roullet, H Homesley, D Belpomme, J Glick
Journal: Journal of Clinical Oncology (1996)

PURPOSE Serious cumulative toxicity is a well-recognized consequence of chemotherapy. Amifostine, an organic thiophosphate, has demonstrated the ability to protect selectively a broad range of normal, but not neoplastic, tissues from the cytotoxic effects of chemotherapy and radiotherapy. This study was designed to determine if amifostine could reduce the serious toxicities associated with cyclophosphamide and cisplatin (CP), without reducing antitumor efficacy in patients with ovarian cancer. PATIENTS AND METHODS Two hundred forty-two patients with advanced ovarian cancer were randomized to receive six cycles of cyclophosphamide (1,000 mg/m2) and cisplatin (100 mg/m2) with or without amifostine (910 mg/m2) every 3 weeks for six cycles. The occurrence of hematologic, renal, neurologic, and ototoxicity was evaluated. Antitumor efficacy was assessed by pathologic tumor response and survival. RESULTS Pretreatment with amifostine before each cycle of chemotherapy resulted in a reduction of cumulative toxicities. Hematologic toxicity consisted of grade 4 neutropenia associated with fever and/or infection that required antibiotic therapy (P = .005), days in hospital (P = .019), and days on antibiotics (P = .031). Platinum-specific toxicities consisted of protracted serum creatinine elevations (P = 0.004), &gt; or = 40% reduction from baseline in creatinine clearance (P = .001), and severity of neurologic toxicity (P = .029). Twenty-four percent of CP patients compared with 9% of amifostine plus CP patients discontinued therapy because of protocol-specified toxicity (P = .002). Pathologic tumor response rates were 37% with amifostine and 28% in controls, with comparable median survival times of 31 months. Amifostine was generally well tolerated; the principal side effects were emesis and a transient decrease in blood pressure. CONCLUSION Pretreatment with amifostine reduces the cumulative hematologic, renal, and neurologic toxicities associated with the CP regimen, with no reduction in antitumor efficacy.
Blockade of the integrin alpha Lbeta 2 but not of integrins alpha 4 and/or beta 7 significantly prolongs intestinal allograft survival in mice
Authors: S Sarnacki
Journal: Gut (2000)

Small bowel transplantation remains a difficult therapeutic option endangered by a high rate of rejection and infectious complications. To improve these clinical results, it is mandatory to set up animal models to test alternative immunosuppressive regimens which may lead to immunotolerance.To determine the value of blockade of alphaLbeta2 (LFA-1) and alpha4 and beta7 integrins (alpha4beta1, alpha4beta7, and alphaEbeta7) in the prevention of rejection of fetal small bowel grafts in mice and the effect of the association of calcineurin dependent drugs in anti-LFA-1 treated mice.Adult recipient mice engrafted with allogeneic fetal small bowel received a short course of anti-alpha4 and/or anti-LFA-1 monoclonal antibodies (mAb) with or without FK506 or cyclosporin A. In addition, in a set of experiment, beta7-/- mice were used as recipients. Graft biopsies were performed and processed for standard histology.Blockade of the pathways of the integrins alpha4 and beta7 had a modest or no effect on intestinal graft survival. In contrast, transitory, short administration of anti-LFA-1 monoclonal antibody alone, when started before engraftment (day -1), allowed long term survival of intestinal grafts, even when associated with calcineurin dependent drugs. However, early withdrawal of FK506 reversed the immunosuppressive effect of anti-LFA-1 treatment.These results suggest that firstly, anti-LFA-1, but not anti-alpha4 mAb treatment, may be useful in improving the results of intestinal transplantation, and secondly, that this treatment is not incompatible with long term administration of tacrolimus currently used in the prevention of small bowel graft rejection in humans.