tbuckley/cabot-search huggingface dataset:
Phase II trial of sunitinib in bevacizumab-refractory metastatic renal cell carcinoma (mRCC): Updated results and analysis of circulating biomarkers
Authors: D. J. George, M. D. Michaelson, J. E. Rosenberg, R. M. Bukowski, J. A. Sosman, W. M. Stadler, K. Margolin, T. E. Hutson, B. I. Rini
Journal: Journal of Clinical Oncology (2007)

5035 Background: Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor with antiangiogenic and antitumor activity. This study evaluated the safety and activity of sunitinib in mRCC patients (pts) previously treated with the VEGF-neutralizing antibody, bevacizumab. Levels of angiogenic biomarkers, including plasma VEGF and soluble VEGFR-3 (sVEGFR-3), were assessed for predictive significance with clinical response. Methods: Pts were required to have mRCC with disease progression following bevacizumab- based therapy, measurable disease, ECOG performance status 0 or 1, and adequate organ function. Pts were treated with sunitinib 50 mg daily in 6-week cycles (4 weeks on, followed by 2 weeks off). The primary endpoint was objective response according to RECIST. Plasma VEGF and sVEGFR-3 levels were measured in pre-treatment samples and at multiple timepoints on study. Results: A total of 61 pts were enrolled. The objective partial response rate was 23% (95% CI: 13%, 36%); 35 pts (57%) demonstrated stable disease. The median duration of response was 36 weeks (95% CI: 26, NA) and progression-free survival was 30 weeks (95% CI: 18, 34). Plasma VEGF levels increased from baseline (3-fold mean elevation), while plasma sVEGFR-3 levels decreased from baseline (40% mean reduction). Pre-treatment VEGF levels were significantly higher in pts (n=34) with &lt;10 weeks between cessation of bevacizumab and start of sunitinib (p&lt;0.001); ELISA specificity suggests that detected VEGF is not bevacizumab-bound. Pre-treatment sVEGFR-3 levels were significantly lower at baseline in responding pts vs. non-responding pts (p&lt;0.0318). A greater reduction in sVEGFR-3 levels was seen in responding pts vs. non-responding pts (p&lt;0.10). Pretreatment VEGF and VEGF fold-changes did not differ according to clinical response. Conclusions: Sunitinib has significant antitumor activity in bevacizumab-refractory mRCC pts, suggesting absence of cross-resistance between bevacizumab and sunitinib. Biomarkers including plasma VEGF and sVEGFR-3 may have predictive potential in sunitinib-treated patients. No significant financial relationships to disclose.
Chemical, Physical, and Biologic Properties of Biosynthetic Human Insulin
Authors: Ronald E Chance, Eugene P Kroeff, James A Hoffmann, Bruce H Frank
Journal: Diabetes Care (1981)

Human insulin derived via recombinant DNA technology was tested extensively by a complex battery of analytic procedures. This product, which is designated biosynthetic human insulin, was found to be chemically, physically, and immunologically equivalent to pancreatic human insulin and biologically equivalent to both pancreatic human insulin and purified pork insulin.
Influences on day-to-day self-management of type 2 diabetes among African-American women: spirituality, the multi-caregiver role, and other social context factors.
Authors: C D Samuel-Hodge, S W Headen, A H Skelly, A F Ingram, T C Keyserling, E J Jackson, A S Ammerman, T A Elasy
Journal: Diabetes Care (2000)

OBJECTIVE: Many African-American women are affected by diabetes and its complications, and culturally appropriate lifestyle interventions that lead to improvements in glycemic control are urgently needed. The aim of this qualitative study was to identify culturally relevant psychosocial issues and social context variables influencing lifestyle behaviors--specifically diet and physical activity--of southern African-American women with diabetes. RESEARCH DESIGN AND METHODS: We conducted 10 focus group interviews with 70 southern African-American women with type 2 diabetes. Group interviews were audiotaped and transcripts were coded using qualitative data analysis software. A panel of reviewers analyzed the coded responses for emerging themes and trends. RESULTS: The dominant and most consistent themes that emerged from these focus groups were 1) spirituality as an important factor in general health, disease adjustment, and coping; 2) general life stress and multi-caregiving responsibilities interfering with daily disease management; and 3) the impact of diabetes manifested in feelings of dietary deprivation, physical and emotional "tiredness," "worry," and fear of diabetes complications. CONCLUSIONS: Our findings suggest that influences on diabetes self-management behaviors of African-American women may be best understood from a sociocultural and family context. Interventions to improve self-management for this population should recognize the influences of spirituality, general life stress, multi-caregiving responsibilities, and the psychological impact of diabetes. These findings suggest that family-centered and church-based approaches to diabetes care interventions are appropriate.
Imaging Tumor Angiogenesis With Contrast Ultrasound and Microbubbles Targeted to α <sub>v</sub> β <sub>3</sub>
Authors: Dilantha B. Ellegala, Howard Leong-Poi, Joan E. Carpenter, Alexander L. Klibanov, Sanjiv Kaul, Mark E. Shaffrey, Jiri Sklenar, Jonathan R. Lindner
Journal: Circulation (2003)

Angiogenesis is a critical determinant of tumor growth and metastasis. We hypothesized that contrast-enhanced ultrasound (CEU) with microbubbles targeted to alpha(v)-integrins expressed on the neovascular endothelium could be used to image angiogenesis.Malignant gliomas were produced in 14 athymic rats by intracerebral implantation of U87MG human glioma cells. On day 14 or day 28 after implantation, CEU was performed with microbubbles targeted to alpha(v)beta3 by surface conjugation of echistatin. CEU perfusion imaging with nontargeted microbubbles was used to derive tumor microvascular blood volume and blood velocity. Vascular alpha(v)-integrin expression was assessed by immunohistochemistry, and microbubble adhesion was characterized by confocal microscopy. Mean tumor size increased markedly from 14 to 28 days (2+/-1 versus 35+/-14 mm2, P<0.001). Tumor blood volume increased by approximately 35% from day 14 to day 28, whereas microvascular blood velocity decreased, especially at the central portions of the tumors. On confocal microscopy, alpha(v)beta3-targeted but not control microbubbles were retained preferentially within the tumor microcirculation. CEU signal from alpha(v)beta3-targeted microbubbles in tumors increased significantly from 14 to 28 days (1.7+/-0.4 versus 3.3+/-1.0 relative units, P<0.05). CEU signal from alpha(v)beta3-targeted microbubbles was greatest at the periphery of tumors, where alpha(v)-integrin expression was most prominent, and correlated well with tumor microvascular blood volume (r=0.86).CEU with microbubbles targeted to alpha(v)beta3 can noninvasively detect early tumor angiogenesis. This technique, when coupled with changes in blood volume and velocity, may provide insights into the biology of tumor angiogenesis and be used for diagnostic applications.
Control of Inhibitory Synaptic Outputs by Low Excitability of Axon Terminals Revealed by Direct Recording
Authors: Shin-ya Kawaguchi, Takeshi Sakaba
Journal: Neuron (2015)

Highlights•Cultured Purkinje cell (PC) axon terminals contain a large RRP of synaptic vesicles•Release probability of RRP vesicles is extremely low in cultured PC axon terminals•Action potentials that conduct reliably along the axon are attenuated close to terminals•Attenuated action potentials control short-term synaptic depressionSummaryAn axon is thought to faithfully conduct action potentials to its terminals. However, many features of the axon and axon terminals, especially at inhibitory synapses, remain unknown. By directly recording from the axon and terminal of a cultured cerebellar Purkinje cell (PC), we demonstrate that low membrane excitability of axon terminals shapes synaptic output. Simultaneous measurements of presynaptic capacitance and evoked IPSCs revealed PC axon terminals contained large readily releasable synaptic vesicles that exhibited a low release probability. Nevertheless, IPSCs evoked by stimulating a PC soma underwent frequency-dependent depression. Direct axonal recordings showed that high-frequency action potentials were faithfully conducted over axonal bifurcations but were attenuated around terminals. Sparse Na+ channels relative to enriched voltage-gated K+ channels in terminals caused short-term depression of IPSCs by reducing Ca2+ influx. Together with confirmation in slice recordings, our findings reveal a presynaptic mechanism that shapes short-term synaptic depression without depleting releasable vesicles.
Genetic variants and the risk of gestational diabetes mellitus: a systematic review
Authors: Cuilin Zhang, Wei Bao, Ying Rong, Huixia Yang, Katherine Bowers, Edwina Yeung, Michele Kiely
Journal: Human Reproduction Update (2013)

BACKGROUNDSeveral studies have examined associations between genetic variants and the risk of gestational diabetes mellitus (GDM). However, inferences from these studies were often hindered by limited statistical power and conflicting results. We aimed to systematically review and quantitatively summarize the association of commonly studied single nucleotide polymorphisms (SNPs) with GDM risk and to identify important gaps that remain for consideration in future studies.
Combined Therapy With Insulin Plus Oral Agents: Is There Any Advantage?
Authors: Matthew C. Riddle
Journal: Diabetes Care (2008)

Physicians in many countries use combinations of antihyperglycemic agents to achieve the best glycemic control possible under the conditions faced by individual patients with type 2 diabetes. This widespread use of combined therapies, including oral agents combined with insulin, suggests that the diabetes community accepts the value of this tactic. A routine need for combined therapies was explicitly acknowledged by the investigators in the U.K. Prospective Diabetes Study. Review of the results of 9 years of monotherapy with various agents in the U.K. Prospective Diabetes Study found that fasting plasma glucose (FPG) was kept below 7.8 mmol/l (140 mg/dl) in only 18% of participants using metformin, 24% using a sulfonylurea, and 42% using insulin (1). Corresponding values for keeping A1C below 7% were 13% with metformin, 24% with a sulfonylurea, and 28% with insulin. Regardless of which agent was used as initial therapy, a progressive worsening of glycemic control ensued, largely because of a gradual decline of endogenous insulin production. A substudy embedded in the U.K. Prospective Diabetes Study compared early addition of basal insulin to a sulfonylurea with insulin alone and showed that over 6 years of treatment the combined regimen achieved lower median A1C (6.6 vs. 7.1%) and also less major hypoglycemia (1.6 vs. 3.2% annually) (2). The U.K. Prospective Diabetes Study investigators concluded that “the majority of patients need multiple therapies to attain these glycemic targets in the longer term” (1).

However, combined therapy with oral agents and insulin has not been accepted as desirable by all experts. This article describes an argument in favor of combined therapy in a recent debate examining the advantages and limitations of this approach. Because reports of various combined regimens have been summarized previously, consistently showing better glycemic control with combined therapy (3–6), this article will not systematically …
Tyrosine Phosphatase PTPN22: Multifunctional Regulator of Immune Signaling, Development, and Disease
Authors: Nunzio Bottini, Erik J. Peterson
Journal: Annual Review of Immunology (2013)

Inheritance of a coding variant of the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene is associated with increased susceptibility to autoimmunity and infection. Efforts to elucidate the mechanisms by which the PTPN22-C1858T variant modulates disease risk revealed that PTPN22 performs a signaling function in multiple biochemical pathways and cell types. Capable of both enzymatic activity and adaptor functions, PTPN22 modulates signaling through antigen and innate immune receptors. PTPN22 plays roles in lymphocyte development and activation, establishment of tolerance, and innate immune cell-mediated host defense and immunoregulation. The disease-associated PTPN22-R620W variant protein is likely involved in multiple stages of the pathogenesis of autoimmunity. Establishment of a tolerant B cell repertoire is disrupted by PTPN22-R620W action during immature B cell selection, and PTPN22-R620W alters mature T cell responsiveness. However, after autoimmune attack has initiated tissue injury, PTPN22-R620W may foster inflammation through modulating the balance of myeloid cell-produced cytokines.
Aldosterone-Induced Coronary Dysfunction in Transgenic Mice Involves the Calcium-Activated Potassium (BKCa) Channels of Vascular Smooth Muscle Cells
Authors: Marie-Lory Ambroisine, Julie Favre, Patricia Oliviero, Camille Rodriguez, Ji Gao, Christian Thuillez, Jane-Lise Samuel, Vincent Richard, Claude Delcayre
Journal: Circulation (2007)

Cardiomyocyte-specific overexpression of aldosterone synthase in male (MAS) mice induces a nitric oxide-independent coronary dysfunction. Because calcium-activated potassium (BKCa) channels are essential for vascular smooth muscle cell (VSMC) relaxation, we hypothesized that aldosterone alters their expression and/or function in VSMCs.Left coronary artery segments were isolated from MAS or male wild-type mice and mounted in a wire myograph. Responses to acetylcholine were assessed (in the presence of a nitric oxide synthase inhibitor) without or with the cyclooxygenase inhibitor diclofenac, the KCa inhibitors charybdotoxin plus apamin, or the BKCa inhibitor iberiotoxin. Expression of BKCa was quantified in hearts by real-time quantitative polymerase chain reaction and Western blot and in isolated coronary arteries by polymerase chain reaction. The effect of aldosterone on BKCa expression also was studied in cultured rat aortic VSMCs. Acetylcholine-mediated coronary relaxation was markedly decreased in MAS mice and was prevented by spironolactone. Diclofenac did not affect the MAS-induced impairment in the responses to acetylcholine, whereas charybdotoxin plus apamin virtually abolished the relaxation in both male wild-type and MAS mice. After iberiotoxin, relaxation to acetylcholine was decreased to a larger extent in male wild-type than in MAS, leading to similar levels of relaxation. BKCa-alpha and -beta1 subunit expressions were significantly decreased in MAS heart and coronary arteries. In cultured VSMCs, aldosterone induced a concentration-dependent decrease in BKCa expression, which was prevented by spironolactone.Aldosterone overexpression altered VSMC BKCa expression and coronary BKCa-dependent relaxation. The resulting alteration of relaxing responses may contribute to the deleterious effects of aldosterone in cardiovascular diseases. BKCa channels may therefore be useful therapeutic targets in cardiovascular diseases.
Précis of From neuropsychology to mental structure
Authors: Tim Shallice
Journal: Behavioral and Brain Sciences (1991)

Abstract Neuropsychological results are increasingly cited in cognitive theories although their methodology has been severely criticised. The book argues for an eclectic approach but particularly stresses the use of single-case studies. A range of potential artifacts exists when inferences are made from such studies to the organisation of normal function – for example, resource differences among tasks, premorbid individual differences, and reorganisation of function. The use of “strong” and “classical” dissociations minimises potential artifacts. The theoretical convergence between findings from fields where cognitive neuropsychology is well developed and those from the normal literature strongly suggests that the potential artifacts are not critical. The fields examined in detail in this respect are short-term memory, reading, writing, the organisation of input and output speech systems, and visual perception. Functional dissociation data suggest that not only are input systems organised modularly, but so are central systems. This conclusion is supported by findings on impairment of knowledge, visual attention, supervisory functions, memory, and consciousness.
Rational home management of diarrhoea
Authors: S. Almroth, M.C. Latham
Journal: The Lancet (1995)

During the 1960s-1970s, treatment of dehydration caused by diarrhea shifted from intravenous (IV) fluid replacement to use of oral rehydration salts (ORS). During diarrhea, glucose through a sodium-coupled transport mechanism and water (ORS solution) improves the ability of the small intestine to absorb fluid. Initially, the international health community ignored the potential usefulness of food, especially carbohydrates and proteins, in preventing and treating dehydration. The leading obstacle to acceptance of allowing food intake during diarrhea was variations in composition of local food staples. Food was almost always excluded during conventional clinical management of diarrhea (i.e., IV therapy). Health workers were advised to withhold food, including breast milk, during the first rehydration phase (first 24 hours). Despite the advice to withhold feeding, mothers in many developing countries continued to feed and breast feed their children during diarrhea with no ill effects. The mothers tended to use cereal-based solutions or breast feed during diarrheal episodes. In the beginning, health personnel were most concerned about access to ORS rather than acceptance. They assumed that oral rehydration therapy (ORT) was relatively easy to use. Experience showed that neither ORS nor home-prepared sugar and salt solutions (SSS) were easy to prepare correctly. In fact, mothers/caretakers often prepared SSS with unsafe high concentrations of sodium. In 1987, WHO developed a guide to help Control of Diarrheal Diseases program managers select home-based fluids that were as ORS-like as possible. Diarrhea cases in hospitals tend to be more severe than those at home. Almost all hospital cases need treatment, while those at home tend to be less severe and only need simple measures to prevent dehydration. Yet, international health specialists designed home-treatment to be like hospital-treatment. This is a restrictive approach. More rational guidelines for ORS have since emerged due to ORS failures at home.
Peripheral Artery Disease, Diabetes, and Reduced Lower Extremity Functioning
Authors: Nancy C. Dolan, Kiang Liu, Michael H. Criqui, Philip Greenland, Jack M. Guralnik, Cheeling Chan, Joseph R. Schneider, Aimee Luna Mandapat, Gary Martin, Mary M. McDermott
Journal: Diabetes Care (2002)

To characterize lower extremity function and dysfunction in peripheral artery disease (PAD) patients with and without diabetes.In this cross-sectional study, 460 men and women with PAD (147 with diabetes) were recruited from three academic medical centers. Assessments included ankle brachial index (ABI), neuropathy score, 6-min walk distance, 4-m walking velocity, Walking Impairment Questionnaire (0-100 scale, 100 = best), and summary performance score (SPS) (0-12 scale, 12 = best).The mean ABI was similar in PAD patients with and without diabetes. PAD patients with diabetes were younger, had a higher BMI, had a worse neuropathy score, and had a greater number of cardiovascular comorbidities compared with those without diabetes. Participants with diabetes were less likely to report classical symptoms of intermittent claudication and more likely to report exertional leg pain, which sometimes started at rest. After adjusting for age, those with diabetes had a shorter mean 6-min walk distance (1,040 vs. 1,168 feet, P < 0.001), slower fast-pace 4-m walk velocity (0.83 vs. 0.90 m/sec, P < 0.001), and a lower SPS (7.3 vs. 8.6, P < 0.001) than those without diabetes. Patients with diet-controlled diabetes performed better than those on diabetes medications. Differences in lower extremity functioning between patients with and without diabetes were largely attenuated but not abolished for SPS and fast-pace 4-m walk velocity after adjustment for type of exertional leg pain, neuropathy score, and number of cardiovascular comorbidities.Subjects with PAD and diabetes have poorer lower extremity function than those with PAD alone. This difference in functioning appears to be largely explained by diabetes-associated neuropathy, differences in exertional leg symptoms, and greater cardiovascular disease in patients with diabetes.
Collaborative Efforts Driving Progress in Pediatric Acute Myeloid Leukemia
Authors: C. Michel Zwaan, Edward A. Kolb, Dirk Reinhardt, Jonas Abrahamsson, Souichi Adachi, Richard Aplenc, Eveline S.J.M. De Bont, Barbara De Moerloose, Michael Dworzak, Brenda E.S. Gibson, Henrik Hasle, Guy Leverger, Franco Locatelli, Christine Ragu, Raul C. Ribeiro, Carmelo Rizzari, Jeffrey E. Rubnitz, Owen P. Smith, Lillian Sung, Daisuke Tomizawa, Marry M. van den Heuvel-Eibrink, Ursula Creutzig, Gertjan J.L. Kaspers
Journal: Journal of Clinical Oncology (2015)

Diagnosis, treatment, response monitoring, and outcome of pediatric acute myeloid leukemia (AML) have made enormous progress during the past decades. Because AML is a rare type of childhood cancer, with an incidence of approximately seven occurrences per 1 million children annually, national and international collaborative efforts have evolved. This overview describes these efforts and includes a summary of the history and contributions of each of the main collaborative pediatric AML groups worldwide. The focus is on translational and clinical research, which includes past, current, and future clinical trials. Separate sections concern acute promyelocytic leukemia, myeloid leukemia of Down syndrome, and relapsed AML. A plethora of novel antileukemic agents that have emerged, including new classes of drugs, are summarized as well. Finally, an important aspect of the treatment of pediatric AML--supportive care--and late effects are discussed. The future is bright, with a wide range of emerging innovative therapies and with more and more international collaboration that ultimately aim to cure all children with AML, with fewer adverse effects and without late effects.
CONTROLLED TRIAL OF STREPTOKINASE AND HEPARIN IN ACUTE MYOCARDIAL INFARCTION
Authors: N. Dioguardi, A. Lotto, G.F. Levi, M. Rota, C. Proto, P.M. Mannucci, P. Rossi, B. Lomanto, G. Mattei, G. Fiorelli, A. Agostoni
Journal: The Lancet (1971)
Foetal hypoxia increases cardiac AT2R expression and subsequent vulnerability to adult ischaemic injury
Authors: Qin Xue, Chiranjib Dasgupta, Man Chen, Lubo Zhang
Journal: Cardiovascular Research (2010)

Hypoxia is a common stress to the foetus and results in increased cardiac vulnerability to adult ischaemic injury. This study tested the hypothesis that foetal hypoxia causes programming of increased AT2 receptor (AT2R) expression in the heart, resulting in the heightened cardiac susceptibility to adult ischaemic injury. Time-dated pregnant rats were divided between normoxic and hypoxic (10.5% O2 from days 15 to 21 of gestation) groups. Hypoxia resulted in significantly increased AT2R in the heart of adult offspring. Multiple glucocorticoid response elements (GREs) were identified at the AT2R promoter, deletion of which increased the promoter activity. Consistently, ex vivo treatment of isolated foetal hearts with dexamethasone for 48 h decreased AT2R expression, which was inhibited by RU 486. Hypoxia decreased glucocorticoid receptors (GRs) in the hearts of foetal, 3-week-old and 3-month-old offspring, resulting in decreased GR binding to the GREs at the AT2R promoter. The inhibition of AT2R improved postischaemic recovery of left ventricular function and rescued the foetal hypoxia-induced cardiac ischaemic vulnerability in male adult animals. In contrast, the inhibition of AT1 receptors decreased the postischaemic recovery. The results demonstrate that in utero hypoxia causes programming of increased AT2R gene expression in the heart by downregulating GR, which contributes to the increased cardiac vulnerability to adult ischaemic injury caused by prenatal hypoxic exposure.