tbuckley/cabot-search huggingface dataset:
Rarity of a Marked “Dawn Phenomenon” in Diabetic Subjects Treated by Continuous Subcutaneous Insulin Infusion
Authors: Jeremy J Bending, John C Pickup, Andrea C G Collins, Harry Keen
Journal: Diabetes Care (1985)

We assessed the quality of overnight glycemic control and the frequency of the “dawn phenomenon” (nadir–0800 h glycemic increase) in 41 insulin-dependent diabetic patients treated by continuous subcutaneous insulin infusion (CSII). Mean plasma glucose levels were near-normal during the 24 h and, in particular, constant throughout the night. In a subset of six patients overnight plasma free insulin concentrations were also constant during CSII. The majority of profiles (88%) showed a glucose nadir from 2.0 to 5.9 mmol/L (most frequently at 0600 h) and had an 0800 h value from 2.0 to 6.9 mmol/L (92%). A large proportion (46%) of profiles showed a zero or negative nadir-0800 h glycemic increase. In 22 patients with three or more profiles recorded at the same basal insulin infusion rate, only one of 103 profiles had a fasting glycemic increase greater than an arbitrary value of 5.0 mmol/L (5.3), although many patients exhibited small dawn glycemic increases (e.g., 14 of 22 had a mean increase of from 0 to 2 mmol/L). In 12 subjects a 15% reduction in basal insulin infusion rate increased the mean ± SEM dawn glycemic increase from 0.58 ± 0.25 mmol/L to 2.7 ± 0.76 mmol/L (P &amp;lt; 0.025) as well as significantly increasing the nocturnal nadir and 0800 h plasma glucose concentrations. Thus, a marked dawn phenomenon is rare when a single but adequate basal infusion rate is used for CSII, and this questions the need in the majority of patients for preprogrammable pumps with nocturnal infusion rate changes.
Accelerated Approval of Oncology Products: A Decade of Experience
Authors: R. Dagher, J. Johnson, G. Williams, P. Keegan, R. Pazdur
Journal: JNCI Journal of the National Cancer Institute (2004)

We review the regulatory history of the accelerated approval process and summarize the U.S. Food and Drug Administration experience with accelerated approvals in oncology. The accelerated approval regulations, promulgated in 1992, allow approval of drugs for serious or life-threatening diseases on the basis of a surrogate endpoint that is reasonably likely to predict clinical benefit, such as survival or symptom benefit, pending completion of studies designed to confirm clinical benefit, referred to as phase 4 commitments, which are required to be conducted with due diligence. From 1992 to 2004, 22 applications involving anticancer drugs or biologics were approved. Of these 22 applications, accelerated approval was granted to 15 on the basis of findings from studies without an active comparator (i.e., single-arm studies or studies comparing two dose levels) and to the remaining seven on the basis of one or more randomized studies. Of the 22 approved applications, six (i.e., applications for dexrazoxane, irinotecan, capecitabine, docetaxel, imatinib mesylate, and oxaliplatin) have had one or more indications converted to regular approval. This review reports information that was presented at an Oncologic Drugs Advisory Committee meeting held in March 2003; it also presents a discussion of accelerated approval study designs, the study populations evaluated in the accelerated approval and confirmatory settings, and the integration of accelerated approval into a comprehensive drug development plan.
THERANOSTICS: From Molecular Imaging Using Ga-68 Labeled Tracers and PET/CT to Personalized Radionuclide Therapy - The Bad Berka Experience
Authors: Richard P. Baum, Harshad R. Kulkarni
Journal: Theranostics (2012)

The acronym THERANOSTICS epitomizes the inseparability of diagnosis and therapy, the pillars of medicine and takes into account personalized management of disease for a specific patient.Molecular phenotypes of neoplasms can be determined by molecular imaging with specific probes using positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), or optical methods, so that the treatment is specifically targeted against the tumor and its environment.To meet these demands, we need to define the targets, ligands, coupling and labeling chemistry, the most appropriate radionuclides, biodistribution modifiers, and finally select the right patients for the personalized treatment.THERANOSTICS of neuroendocrine tumors (NETs) using Ga-68 labeled tracers for diagnostics with positron emission tomography/ computed tomography (PET/CT), and using Lu-177 or other metallic radionuclides for radionuclide therapy by applying the same peptide proves that personalized radionuclide therapy today is already a fact and not a fiction.
Adhesion of T lymphoblasts to epidermal keratinocytes is regulated by interferon gamma and is mediated by intercellular adhesion molecule 1 (ICAM-1).
Authors: M L Dustin, K H Singer, D T Tuck, T A Springer
Journal: The Journal of Experimental Medicine (1988)

The cell surface expression and function of the LFA-1 ligand, intercellular adhesion molecule 1 (ICAM-1), on epidermal keratinocytes (EK) was studied. ICAM-1 expression on the surface of cultured EK was either absent or weak, but was induced by treating EK with rIFN-gamma or TNF for 4-48 h. IFN-gamma and TNF were synergistic. IFN-gamma treatment increased T lymphoblast adhesion from less than 2% to 20-40%, with a concentration dependence similar to that seen for ICAM-1 induction. All of the adhesion to EK was inhibited by LFA-1 and ICAM-1 mAbs, but not by HLA-DR, CD2, or LFA-3 mAbs. There was no difference in the level of T lymphoblast adhesion to IFN-gamma-treated allogeneic or autologous EK. ICAM-1 purified from the HeLa epithelioid cell line and reconstituted into planar membranes also supported efficient adhesion of T lymphoblasts that was blocked by LFA-1 mAb bound to the T lymphoblasts or ICAM-1 mAb bound to the planar membranes. T lymphoblasts adherent to EK or ICAM-1 planar membranes were isolated by panning, and surface markers were analyzed by immunofluorescence flow cytometry. The adherent T cells were a phenotypically skewed subpopulation. They were enriched for CD8+ cells and expressed 1.5-2.5-fold higher LFA-1 and CD2 compared with the unseparated population.
Ethanol increases the formation of NADP+ in rat hepatocytes
Authors: Emmanuel B. Akinshola, James J. Potter, Esteban Mezey
Journal: Hepatology (1991)

The acute effects of ethanol on total (bound + free) pyridine dinucleotides were determined in freshly isolated rat hepatocytes. Pyridine dinucleotides and adenine nucleotides were determined by high-performance liquid chromatography. Exposure of the hepatocytes to 8 mmol/L ethanol resulted in a decrease in NAD+ and an increase in NADP+ after 2 min incubation. There were no significant changes in NADH and NADPH. Ethanol decreased ATP and increased AMP after 2 min, whereas an increase in ADP was only apparent after 15 min of incubation. Ethanol 8 mmol/L and 100 mmol/L resulted in an increased incorporation of [32P] into NADP+ from [32P]-prelabeled NAD+ and ATP. Ethanol increased hepatocyte NAD+ kinase activity; this effect was blocked by 4-methylpyrazole but reproduced by 10 mumol acetaldehyde. These observations indicate that ethanol increases the synthesis of NADP+ and that this effect is most likely the result of increased NAD+ kinase activity. The ethanol-induced decrease of NAD+ may limit ADP ribosylation of nuclear proteins, whereas increases in NADP+ may stimulate the pentose phosphate cycle.
A Rb1 promoter variant with reduced activity contributes to osteosarcoma susceptibility in irradiated mice
Authors: Michael Rosemann, Iria Gonzalez-Vasconcellos, Tanja Domke, Virginija Kuosaite, Ralf Schneider, Markus Kremer, Jack Favor, Michaela Nathrath, Michael J Atkinson
Journal: Molecular Cancer (2014)

Syndromic forms of osteosarcoma (OS) account for less than 10% of all recorded cases of this malignancy. An individual OS predisposition is also possible by the inheritance of low penetrance alleles of tumor susceptibility genes, usually without evidence of a syndromic condition. Genetic variants involved in such a non-syndromic form of tumor predisposition are difficult to identify, given the low incidence of osteosarcoma cases and the genetic heterogeneity of patients. We recently mapped a major OS susceptibility QTL to mouse chromosome 14 by comparing alpha-radiation induced osteosarcoma in mouse strains which differ in their tumor susceptibility. Tumor-specific allelic losses in murine osteosacoma were mapped along chromosome 14 using microsatellite markers and SNP allelotyping. Candidate gene search in the mapped interval was refined using PosMed data mining and mRNA expression analysis in normal osteoblasts. A strain-specific promoter variant in Rb 1 was tested for its influence on mRNA expression using reporter assay. A common Rb1 allele derived from the BALB/cHeNhg strain was identified as the major determinant of radiation-induced OS risk at this locus. Increased OS-risk is linked with a hexanucleotide deletion in the promoter region which is predicted to change WT1 and SP1 transcription factor-binding sites. Both in-vitro reporter and in-vivo expression assays confirmed an approx. 1.5 fold reduced gene expression by this promoter variant. Concordantly, the 50% reduction in Rb1 expression in mice bearing a conditional hemizygous Rb1 deletion causes a significant rise of OS incidence following alpha-irradiation. This is the first experimental demonstration of a functional and genetic link between reduced Rb1 expression from a common promoter variant and increased tumor risk after radiation exposure. We propose that a reduced Rb1 expression by common variants in regulatory regions can modify the risk for a malignant transformation of bone cells after radiation exposure.
Evaluation of the SCA instrument for measuring patient satisfaction with cancer care administered via paper or via the Internet
Authors: N. Kamo, S.V. Dandapani, R.A. Miksad, M.J. Houlihan, I. Kaplan, M. Regan, T.K. Greenfield, M.G. Sanda
Journal: Annals of Oncology (2010)

Patients' perspectives provide valuable information on quality of care. This study evaluates the feasibility and validity of Internet administration of Service Satisfaction Scale for Cancer Care (SCA) to assess patient satisfaction with outcome, practitioner manner/skill, information, and waiting/access.Primary data collected from November 2007 to April 2008. Patients receiving cancer care within 1 year were recruited from oncology, surgery, and radiation clinics at a tertiary care hospital. An Internet-based version of the 16-item SCA was developed. Participants were randomised to Internet SCA followed by paper SCA 2 weeks later or vice versa. Seven-point Likert scale responses were converted to a 0-100 scale (minimum-maximum satisfaction). Response distribution, Cronbach's alpha, and test-retest correlations were calculated.Among 122 consenting participants, 78 responded to initial SCA. Mean satisfaction scores for paper/Internet were 91/90 (outcome), 95/94 (practitioner manner/skill), 89/90 (information), and 86/86 (waiting/access). Response rate and item missingness were similar for Internet and paper. Except for practitioner manner/skill, test-retest correlations were robust r = 0.77 (outcome), 0.74 (information), and 0.75 (waiting/access) (all P < 0.001).Internet SCA administration is a feasible and a valid measurement of cancer care satisfaction for a wide range of cancer diagnoses, treatment modalities, and clinic settings.
Science on Trial: The Clash of Medical Evidence and the Law in the Breast Implant Case
Authors: J A M. Gray
Journal: BMJ (1996)

M Angell W W Norton, £22 (to be published January 1997), pp 256 ISBN 0 393 03973 0

Atrend in American litigation has important implications not only for those who practise medicine but also for those who purchase and organise it and for those who make equipment that clinicians use. By describing one particular case in the United States courts, this book focuses on the clash between medical and legal definitions of evidence that has received little attention hitherto but which is relevant world wide.

The story itself is relatively simple. A few women claimed that health problems, notably connective tissue disease, had resulted from their breast implants. A few “expert” witnesses asserted that this was the case and propounded theories about how such a causal relation might operate. There was not, and never has been, any strong evidence based on good epidemiological research that breast implants actually cause connective tissue disease, using conventional criteria for defining a causal relation. On the basis …
Follistatin Suppresses the Production of Experimental Multiple-Organ Metastasis by Small Cell Lung Cancer Cells in Natural Killer Cell–Depleted SCID Mice
Authors: Hirokazu Ogino, Seiji Yano, Soji Kakiuchi, Hiroaki Muguruma, Kenji Ikuta, Masaki Hanibuchi, Hisanori Uehara, Kunihiro Tsuchida, Hiromu Sugino, Saburo Sone
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Follistatin (FST), an inhibitor of activin, regulates a variety of biological functions, including cell proliferation, differentiation, and apoptosis. However, the role of FST in cancer metastasis is still unknown. Previous research established a multiple-organ metastasis model of human small cell lung cancer in natural killer cell–depleted SCID mice. In this model, i.v. inoculated tumor cells produced metastatic colonies in multiple organs including the lung, liver, and bone. The purpose of this study is to determine the role of FST in multiple-organ metastasis using this model. Experimental Design: A human FST gene was transfected into the small cell lung cancer cell lines SBC-3 and SBC-5 and established transfectants secreting biologically active FST. The metastatic potential of the transfectants was evaluated using the metastasis model. Results: FST-gene transfection did not affect the cell proliferation, motility, invasion, or adhesion to endothelial cells in vitro. I.v. inoculated SBC-3 or SBC-5 cells produced metastatic colonies into multiple organs, including the lung, liver, and bone in the natural killer cell–depleted SCID mice. FST transfectants produced significantly fewer metastatic colonies in these organs when compared with their parental cells or vector control clones. Immunohistochemical analyses of the liver metastases revealed that the number of proliferating tumor cells and the tumor-associated microvessel density were significantly less in the lesions produced by FST transfectants. Conclusions: These results suggest that FST plays a critical role in the production of multiple-organ metastasis, predominantly by inhibiting the angiogenesis. This is the first report to show the role of FST in metastases.
Abrogating Drug Resistance in Malignant Peripheral Nerve Sheath Tumors by Disrupting Hyaluronan-CD44 Interactions with Small Hyaluronan Oligosaccharides
Authors: Mark G. Slomiany, Lu Dai, Paul A. Bomar, Thomas J. Knackstedt, D. Alex Kranc, Lauren Tolliver, Bernard L. Maria, Bryan P. Toole
Journal: Cancer Research (2009)

Malignant peripheral nerve sheath tumors (MPNST) develop in approximately 10% of neurofibromatosis type-1 patients and are a major contributing factor to neurofibromatosis-1 patient mortality and morbidity. MPNSTs are multidrug resistant, and thus long-term patient survival rates are poor after standard doxorubicin or multiagent chemotherapies. We show that the hyaluronan receptor CD44 forms complexes with multidrug transporters, BCRP (ABCG2) and P-glycoprotein (ABCB1), in the plasma membrane of human MPNST cells. Small hyaluronan oligosaccharides antagonize hyaluronan-CD44-mediated processes and inhibit hyaluronan production. Treatment of MPNST cells with the hyaluronan oligomers causes disassembly of CD44-transporter complexes and induces internalization of CD44, BCRP, and P-glycoprotein. Consequently, the oligomers suppress drug transporter activity and increase sensitivity to doxorubicin treatment in culture. In vivo, systemic administration of hyaluronan oligomers inhibits growth of MPNST xenografts. Moreover, the oligomers and doxorubicin act synergistically in vivo, in that combined suboptimal doses induce tumor regression to a greater extent than the additive effects of each agent alone. These findings indicate that constitutive hyaluronan-CD44 interactions contribute to drug transporter localization and function at the plasma membrane, and that attenuating hyaluronan-CD44 interactions sensitizes MPNSTs to doxorubicin in vitro and in vivo. These results also show the potential efficacy of hyaluronan oligomers, which are nontoxic and nonimmunogenic, as an adjuvant for chemotherapy in MPNST patients.
Male pseudohermaphroditism due to a homozygous missense mutation of the luteinizing hormone receptor gene
Authors: Hannie Kremer, Robert Kraaij, Sergio P.A. Toledo, Miriam Post, Julia B. Fridman, Cesar Y. Hayashida, Margo van Reen, Edwin Milgrom, Hans-Hilger Ropers, Edwin Mariman, Axel P.N. Themmen, Han G. Brunner
Journal: Nature Genetics (1995)
Intracellular localization of Rickettsia tsutsugamushi in polymorphonuclear leukocytes.
Authors: Y Rikihisa, S Ito
Journal: The Journal of Experimental Medicine (1979)

Rickettsia tsutsugamushi (Gilliam strain) was serially propagated in BHK-21 cell cultures and incubated with guinea pig peritoneal polymorphonuclear leukocytes to study the ultrastructural features of rickettsial uptake and entry into the leukocytes. Significant numbers of rickettsiae were phagocytized selectively by these leukocytes within 30 min. About one-half of these rickettsiae remained sequestered in phagosomes but the other one-half were free from the phagosome and localized directly in the polymorphonuclear leukocyte cytoplasm. Various stages of rickettsial release from the phagosomes were observed. Once free within the polymorphonuclear leukocyte cytoplasm, the rickettsiae were preferentially localized in the glycogen-packed areas which are devoid of lysosomes and other cytoplasmic organelles. This study indicates that rickettsiae phagocytized by polymorphonuclear leukocytes can escape from the phagosome into the cytoplasm.
Dose dependent and divergent effects of superoxide anion on cell death, proliferation, and migration of activated human hepatic stellate cells
Authors: E Novo
Journal: Gut (2005)

<b>Background and aim:</b> Activated myofibroblast-like cells, originating from hepatic stellate cells (HSC/MFs) or other cellular sources, play a key profibrogenic role in chronic liver diseases (CLDs) that, as suggested by studies in animal models or rat HSC/MFs, may be modulated by reactive oxygen intermediates (ROI). In this study, human HSC/MFs, exposed to different levels of superoxide anion (O<sub>2</sub><sup>•−</sup>) and, for comparison, hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), were analysed in terms of cytotoxicity, proliferative response, and migration. <b>Methods:</b> Cultured human HSC/MFs were exposed to controlled O<sub>2</sub><sup>•−</sup> generation by hypoxanthine/xanthine oxidase systems or to a range of H<sub>2</sub>O<sub>2</sub> concentrations. Induction of cell death, proliferation, and migration were investigated using morphology, molecular biology, and biochemical techniques. <b>Results:</b> Human HSC/MFs were shown to be extremely resistant to induction of cell death by O<sub>2</sub><sup>•−</sup> and only high rates of O<sub>2</sub><sup>•−</sup> generation induced either necrotic or apoptotic cell death. Non-cytotoxic low levels of O<sub>2</sub><sup>•−</sup>, able to upregulate procollagen type I expression (but not tissue inhibitor of metalloproteinase 1 and 2), stimulated migration of human HSC/MFs in a Ras/extracellular regulated kinase (ERK) dependent, antioxidant sensitive way, without affecting basal or platelet derived growth factor (PDGF) stimulated cell proliferation. Non-cytotoxic levels of H<sub>2</sub>O<sub>2</sub> did not affect Ras/ERK or proliferative response. A high rate of O<sub>2</sub><sup>•−</sup> generation or elevated levels of H<sub>2</sub>O<sub>2 </sub>induced cytoskeletal alterations, block in motility, and inhibition of PDGF dependent DNA synthesis. <b>Conclusions:</b> Low non-cytotoxic levels of extracellularly generated O<sub>2</sub><sup>•−</sup> may stimulate selected profibrogenic responses in human HSC/MFs without affecting proliferation.
Granulocyte-colony stimulating factor increases CD123hi blood dendritic cells with altered CD62L and CCR7 expression
Authors: Slavica Vuckovic, Min Kim, Dailal Khalil, Cameron J. Turtle, Georgina V. Crosbie, Noel Williams, Len Brown, Katrina Williams, Cathryn Kelly, Penny Stravos, Robyn Rodwell, Geoff R. Hill, Susan Wright, Kerry Taylor, Devinder Gill, Paula Marlton, Ken Bradstock, Derek N. J. Hart
Journal: Blood (2003)
PSYCHOSOCIAL CORRELATES OF DIETARY INTAKE: Advancing Dietary Intervention
Authors: Tom Baranowski, Karen Weber Cullen, Janice Baranowski
Journal: Annual Review of Nutrition (1999)

▪ Abstract Psychosocial variables that predict dietary behavior become important targets for change in nutrition education programs. Psychosocial variables in models with higher predictability provide more effective levers to promote healthy dietary change. A review of the literature on models with psychosocial variables predicting dietary fat and fruit and vegetable consumption revealed generally low predictiveness, R 2 &lt; 0.3 (where R 2 is the squared multiple correlation of the statistical model). No single theory provided models that regularly out-predicted others. When models predicted narrower categories of behavior (e.g. milk or salad consumption), predictiveness tended to be higher. Substantial problems were revealed in the psychometrics of both the independent and dependent variables. Little theory-based research has been conducted with adolescents, and the few studies done with children had low predictiveness. In order to increase the predictiveness of models, future research should combine variables from several theories, attend to the psychometrics of all variables, and incorporate variables that moderate the relationship of psychosocial to dietary behavior (e.g. genetics of taste, stage in the life course). Refinements on current research would include longitudinal designs and use of non–self-report methods of dietary behavior to supplement the self-report methods. Improved understanding of dietary behavior should lead to more effective dietary behavior change interventions.