tbuckley/cabot-search huggingface dataset:
Phase I Trial, Pharmacokinetics, and Pharmacodynamics of Vandetanib and Dasatinib in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma
Authors: Alberto Broniscer, Sharyn D. Baker, Cynthia Wetmore, Atmaram S. Pai Panandiker, Jie Huang, Andrew M. Davidoff, Arzu Onar-Thomas, John C. Panetta, Thomas K. Chin, Thomas E. Merchant, Justin N. Baker, Sue C. Kaste, Amar Gajjar, Clinton F. Stewart
Journal: Clinical Cancer Research (2013)

Testing of promising drug combinations is crucial in the treatment of diffuse intrinsic pontine glioma (DIPG). As the VEGF and platelet-derived growth factor (PDGF) pathways are critical in gliomas, we evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of vandetanib, a VEGFR-2 inhibitor, combined with dasatinib, a potent PDGFR inhibitor, during and after radiotherapy in children with newly diagnosed DIPG.Dasatinib was started concurrently with radiotherapy. Vandetanib was started 8 days later. We tested increasing doses of vandetanib (65 and 85 mg/m(2) once daily) and dasatinib (65 and 85 mg/m(2) twice daily). Dose-limiting toxicities were evaluated during the first 6 weeks of therapy. Plasma pharmacokinetics was obtained on days 8 and 42 ± 3 in all patients and concomitantly with cerebrospinal fluid (CSF) when possible. Inhibition of targets of dasatinib in peripheral blood mononuclear cells (PBMC) was evaluated.Twenty-five patients were treated. Treatment was well tolerated. The median duration of treatment was 184 days. Diarrhea was the most significant toxicity. Three patients experienced substantial myelosuppression. The steady-state plasma pharmacokinetics of vandetanib was comparable with previous studies. Although the plasma exposure to dasatinib decreased from days 8 to 42, it remained similar to adult studies. CSF to plasma exposure of vandetanib and dasatinib were approximately 2% in 2 patients. Phosphorylated 70S6K decreased during therapy in PBMCs.The MTD of vandetanib and dasatinib in combination was 65 mg/m(2) for each drug. Other studies are underway to test dasatinib and other PDGFR inhibitors alone or in combination for this deadly cancer.
MRI Study of Caudate Nucleus Volume and Its Cognitive Correlates in Neuroleptic-Naive Patients With Schizotypal Personality Disorder
Authors: James J. Levitt, Robert W. McCarley, Chandlee C. Dickey, Martina M. Voglmaier, Margaret A. Niznikiewicz, Larry J. Seidman, Yoshio Hirayasu, Aleksandra A. Ciszewski, Ron Kikinis, Ferenc A. Jolesz, Martha E. Shenton
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: "Cognitive" circuits anatomically link the frontal lobe to subcortical structures; therefore, pathology in any of the core components of these circuits, such as in the caudate nucleus, may result in neurobehavioral syndromes similar to those of the frontal lobe. Neuroleptic medication, however, affects the size of the caudate nucleus. For this reason, individuals diagnosed with schizotypal personality disorder offer an ideal group for the measurement of the caudate nucleus because they may be genetically related to individuals with schizophrenia but do not require neuroleptic treatment because of their less severe symptoms. METHOD: Magnetic resonance imagining (MRI) scans obtained on a 1.5-T magnet with 1.5-mm contiguous slices were used to measure the caudate nucleus and lateral ventricles in 15 right-handed male subjects with schizotypal personality disorder who had no previous neuroleptic exposure and in 14 normal comparison subjects. Subjects were group matched for parental socioeconomic status, handedness, and gender. RESULTS: First, the authors found significantly lower left and right absolute (13.1%, 13.2%) and relative (9.1%, 9.2%) caudate nucleus volumes in never-medicated subjects with schizotypal personality disorder than in normal subjects. Second, they found significant, inverse correlations between caudate nucleus volume and the severity of perseveration in two distinct working memory tasks in these neuroleptic-naive subjects with schizotypal personality disorder. CONCLUSIONS: These data are consistent with the findings of reduced caudate nucleus volume reported in studies of neuroleptic-naive patients experiencing their first episode of schizophrenia and support the association of intrinsic pathology in the caudate nucleus with abnormalities in working memory in the schizophrenia spectrum.
THE FACTORS CONCERNED IN THE APPEARANCE OF NUCLEATED RED BLOOD CORPUSCLES IN THE PERIPHERAL BLOOD
Authors: Cecil K. Drinker, Katherine R. Drinker, Henry A. Kreutzmann
Journal: The Journal of Experimental Medicine (1918)

1. Hemorrhage with immediate saline infusion causes the appearance in the peripheral blood of a slightly increased number of normoblasts provided normoblasts are already present in the blood stream. Marrow hyperplasia does not intensify this reaction and the cells found probably do not leave the marrow pulp but are in the blood stream at the time of the experiment. 2. The slight increase in cells occurring immediately after hemorrhage and infusion is designated a pseudocrisis. True crises are much more extensive; they tend to occur just before rapid increase in the erythrocyte count and usually towards the end of the 1st week following hemorrhage. 3. Red cells and white cells tend to move from the marrow together, but this association is not invariable. 4. After repeated hemorrhages regeneration occurs independently of the appearance of nucleated red cells in the peripheral blood. 5. Repeated hemorrhages associated with extension of erythrocyteproducing marrow lead to polycythemia but not to a conspicuous increase in speed of regeneration.
A Destructive Cascade Mediated by CCL2 Facilitates Prostate Cancer Growth in Bone
Authors: Xin Li, Robert Loberg, Jinhui Liao, Chi Ying, Linda A. Snyder, Kenneth J. Pienta, Laurie K. McCauley
Journal: Cancer Research (2009)

Abstract Monocyte chemoattractant protein 1 (CCL2) is a recently identified prominent regulator of prostate cancer growth and metastasis. The purpose of this study was to investigate the mechanistic role of CCL2 in prostate cancer growth in bone. The present study found that CCL2 was up-regulated in osteoblasts (3-fold by PC-3 and 2-fold by VCaP conditioned medium) and endothelial cells (2-fold by PC-3 and VCaP conditioned medium). Parathyroid hormone-related protein (PTHrP) treatment of osteoblastic cells up-regulated CCL2 and was blocked by a PTHrP antagonist, suggesting that prostate cancer–derived PTHrP plays an important role in elevation of osteoblast-derived CCL2. CCL2 indirectly increased blood vessel formation in endothelial cells through vascular endothelial growth factor-A, which was up-regulated 2-fold with administration of CCL2 in prostate cancer cells. In vivo, anti-CCL2 treatment suppressed tumor growth in bone. The decreased tumor burden was associated with decreased bone resorption (serum TRAP5b levels were decreased by 50–60% in anti–CCL2-treated animals from VCaP or PC-3 cell osseous lesions) and microvessel density was decreased by 70% in anti–CCL2-treated animals with bone lesions from VCaP cells. These data suggest that a destructive cascade is driven by tumor cell–derived, PTHrP-mediated induction of CCL2, which facilitates tumor growth via enhanced osteoclastic and endothelial cell activity in bone marrow. Taken together, CCL2 mediates the interaction between tumor-derived factors and host-derived chemokines acting in cooperation to promote skeletal metastasis. [Cancer Res 2009;69(4):1685–92]
Recent Advances in the Treatment of Malignant Astrocytoma
Authors: David A. Reardon, Jeremy N. Rich, Henry S. Friedman, Darell D. Bigner
Journal: Journal of Clinical Oncology (2006)

Malignant gliomas, including the most common subtype, glioblastoma multiforme (GBM), are among the most devastating of neoplasms. Their aggressive infiltration in the CNS typically produces progressive and profound disability--ultimately leading to death in nearly all cases. Improvement in outcome has been elusive despite decades of intensive clinical and laboratory research. Surgery and radiotherapy, the traditional cornerstones of therapy, provide palliative benefit, while the value of chemotherapy has been marginal and controversial. Limited delivery and tumor heterogeneity are two fundamental factors that have critically hindered therapeutic progress. A novel chemoradiotherapy approach, consisting of temozolomide administered concurrently during radiotherapy followed by adjuvant systemic temozolomide, has recently demonstrated a meaningful, albeit modest, improvement in overall survival for newly diagnosed GBM patients. As cell-signaling alterations linked to the development and progression of gliomas are being increasingly elucidated, targeted therapies have rapidly entered preclinical and clinical evaluation. Responses to therapies that function via DNA damage have been associated with specific mediators of resistance that may also be subject to targeted therapies. Other approaches include novel locoregional delivery techniques to overcome barriers of delivery. The simultaneous development of multiple advanced therapies based on specific tumor biology may finally offer glioma patients improved survival.
Engineered In Vitro Disease Models
Authors: Kambez H. Benam, Stephanie Dauth, Bryan Hassell, Anna Herland, Abhishek Jain, Kyung-Jin Jang, Katia Karalis, Hyun Jung Kim, Luke MacQueen, Roza Mahmoodian, Samira Musah, Yu-suke Torisawa, Andries D. van der Meer, Remi Villenave, Moran Yadid, Kevin K. Parker, Donald E. Ingber
Journal: Annual Review of Pathology Mechanisms of Disease (2015)

The ultimate goal of most biomedical research is to gain greater insight into mechanisms of human disease or to develop new and improved therapies or diagnostics. Although great advances have been made in terms of developing disease models in animals, such as transgenic mice, many of these models fail to faithfully recapitulate the human condition. In addition, it is difficult to identify critical cellular and molecular contributors to disease or to vary them independently in whole-animal models. This challenge has attracted the interest of engineers, who have begun to collaborate with biologists to leverage recent advances in tissue engineering and microfabrication to develop novel in vitro models of disease. As these models are synthetic systems, specific molecular factors and individual cell types, including parenchymal cells, vascular cells, and immune cells, can be varied independently while simultaneously measuring system-level responses in real time. In this article, we provide some examples of these efforts, including engineered models of diseases of the heart, lung, intestine, liver, kidney, cartilage, skin and vascular, endocrine, musculoskeletal, and nervous systems, as well as models of infectious diseases and cancer. We also describe how engineered in vitro models can be combined with human inducible pluripotent stem cells to enable new insights into a broad variety of disease mechanisms, as well as provide a test bed for screening new therapies.
Effect of Corticosteroids on Treatment Failure Among Hospitalized Patients With Severe Community-Acquired Pneumonia and High Inflammatory Response
Authors: Antoni Torres, Oriol Sibila, Miquel Ferrer, Eva Polverino, Rosario Menendez, Josep Mensa, Albert Gabarrús, Jacobo Sellarés, Marcos I. Restrepo, Antonio Anzueto, Michael S. Niederman, Carles Agustí
Journal: JAMA (2015)

IMPORTANCEIn patients with severe community-acquired pneumonia, treatment failure is associated with excessive inflammatory response and worse outcomes.Corticosteroids may modulate cytokine release in these patients, but the benefit of this adjunctive therapy remains controversial.OBJECTIVE To assess the effect of corticosteroids in patients with severe communityacquired pneumonia and high associated inflammatory response.DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, placebo-controlled trial conducted in 3 Spanish teaching hospitals involving patients with both severe community-acquired pneumonia and a high inflammatory response, which was defined as a level of C-reactive protein greater than 150 mg/L at admission.Patients were recruited and followed up from June 2004 through February 2012.INTERVENTIONS Patients were randomized to receive either an intravenous bolus of 0.5 mg/kg per 12 hours of methylprednisolone (n = 61) or placebo (n = 59) for 5 days started within 36 hours of hospital admission.MAIN OUTCOMES AND MEASURES The primary outcome was treatment failure (composite outcome of early treatment failure defined as [1] clinical deterioration indicated by development of shock, [2] need for invasive mechanical ventilation not present at baseline, or [3] death within 72 hours of treatment; or composite outcome of late treatment failure defined as [1] radiographic progression, [2] persistence of severe respiratory failure, [3] development of shock, [4] need for invasive mechanical ventilation not present at baseline , or [5] death between 72 hours and 120 hours after treatment initiation; or both early and late treatment failure).In-hospital mortality was a secondary outcome and adverse events were assessed. RESULTSThere was less treatment failure among patients from the methylprednisolone group (8 patients [13%]) compared with the placebo group (18 patients [31%]) (P = .02),with a difference between groups of 18% (95% CI, 3% to 32%).Corticosteroid treatment reduced the risk of treatment failure (odds ratio, 0.34 [95% CI, 0.14 to 0.87]; P = .02).In-hospital mortality did not differ between the 2 groups (6 patients [10%] in the methylprednisolone group vs 9 patients [15%] in the placebo group; P = .37);the difference between groups was 5% (95% CI, -6% to 17%).Hyperglycemia occurred in 11 patients (18%) in the methylprednisolone group and in 7 patients (12%) in the placebo group (P = .34).CONCLUSIONS AND RELEVANCE Among patients with severe community-acquired pneumonia and high initial inflammatory response, the acute use of methylprednisolone compared with placebo decreased treatment failure.If replicated, these findings would support the use of corticosteroids as adjunctive treatment in this clinical population.
Inhibition by carotid baroreflex of exercise-induced increases in arterial pressure.
Authors: S C Walgenbach, D E Donald
Journal: Circulation Research (1983)

Mean arterial blood pressure, heart rate, and cardiac output were measured during continuous graded exercise (5.5 km/hr; 0, 7, 14, and 21% grades) in conscious dogs, under each of the following four conditions: (1) baroreceptors intact, (2) chronic aortic arch denervation, (3) chronic aortic arch denervation and surgical preparation of the carotid sinuses for later reversible vascular isolation, and (4) chronic aortic arch denervation and carotid sinuses vascularly isolated at a fixed pressure. Arterial blood pressure increased with increasing work load to a maximum of 12 +/- 3, 18 +/- 5, and 14 +/- 5 mm Hg above control in conditions 1, 2, and 3, respectively. In condition 4, the maximum increase in pressure during graded exercise was 51 +/- 7 mm Hg above control. Upon cessation of graded exercise, the increase in arterial pressure persisted through the 5-minute recovery period. Heart rate and cardiac output increased similarly in proportion to work load under all four conditions. In contrast to dogs in condition 4, three dogs with chronic sinoaortic denervation showed no work load-related increase in arterial pressure during exercise. Thus, during exercise, the carotid baroreflex acts to balance finely the opposing effects of sympathetic vasoconstriction and metabolic vasodilation.
Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors
Authors: Frédéric Preitner, Mark Ibberson, Isobel Franklin, Christophe Binnert, Mario Pende, Asllan Gjinovci, Tanya Hansotia, Daniel J. Drucker, Claes Wollheim, Rémy Burcelin, Bernard Thorens
Journal: Journal of Clinical Investigation (2004)

The role of the gluco-incretin hormones GIP and GLP-1 in the control of β cell function was studied by analyzing mice with inactivation of each of these hormone receptor genes, or both. Our results demonstrate that glucose intolerance was additively increased during oral glucose absorption when both receptors were inactivated. After intraperitoneal injections, glucose intolerance was more severe in double- as compared to single-receptor KO mice, and euglycemic clamps revealed normal insulin sensitivity, suggesting a defect in insulin secretion. When assessed in vivo or in perfused pancreas, insulin secretion showed a lack of first phase in Glp-1R–/– but not in Gipr–/– mice. In perifusion experiments, however, first-phase insulin secretion was present in both types of islets. In double-KO islets, kinetics of insulin secretion was normal, but its amplitude was reduced by about 50% because of a defect distal to plasma membrane depolarization. Thus, gluco-incretin hormones control insulin secretion (a) by an acute insulinotropic effect on β cells after oral glucose absorption (b) through the regulation, by GLP-1, of in vivo first-phase insulin secretion, probably by an action on extra-islet glucose sensors, and (c) by preserving the function of the secretory pathway, as evidenced by a β cell autonomous secretion defect when both receptors are inactivated.
T-lymphocyte response to cytochrome c. I. Demonstration of a T-cell heteroclitic proliferative response and identification of a topographic antigenic determinant on pigeon cytochrome c whose immune recognition requires two complementing major histocompatibility complex-linked immune response genes.
Authors: A M Solinger, M E Ultee, E Margoliash, R H Schwartz
Journal: The Journal of Experimental Medicine (1979)

The T-lymphocyte proliferative response to pigeon cytochrome c was studied in the mouse. H-2a and H-2k strains were responders to this antigen whereas H-2b, H-2d, H-2f, H-2ja, H-2p, H-2q, H-2r, H-2s, and H-2u strains were low or nonresponders. Genetic mapping demonstrated that two major histocompatibility complex (MHC)-linked Ir genes control the response, one in I-A, the other in I-E/I-C. The major antigenic determinant recognized in this response was localized by cross-stimulations with species variants and cyanogen bromide cleavage fragments of cytochrome c. It was found to be a topographic surface determinant composed of an isoleucine for valine substitution at residue 3, a glutamine for lysine substitution at residue 100 and a lysine for glutamic acid substitution at residue 104. Tobacco hornworm moth cytochrome c, which contains a glutamine at residue 100 but a terminal lysine at residue 103 (one amino acid closer to the glutamine), stimulated pigeon cytochrome c immune T cells better than the immunogen. This result demonstrates for the first time a functional T-cell heteroclitic proliferative response in a system under Ir gene control. Immunization with the cyanogen bromide cleavage fragments revealed that only pigeon cytochrome c fragment 81-104 was immunogenic. This fragment primed for a T-cell proliferative response whose specificity was nearly identical to that of the T-cell response primed for by the whole molecule, suggesting that the glutamine at 100 and the lysine at 104 form the immunodominant portion of the antigenic site. Furthermore, mixing experiments using the two cross-reacting antigens, hippopotamus cytochrome c and Pekin duck or chicken cytochrome c fragment (81-104), each of which contains only one of the two immunodominant substitutions, demonstrated that the T lymphocytes responding to the major antigenic determinant comprise a single family of clones that recognize both amino acids as part of the same determinant. Thus, two complementing MHC-linked Ir genes can control the immune response to a single antigenic determinant.
Toll-Like Receptors on Tumor Cells Facilitate Evasion of Immune Surveillance
Authors: Bo Huang, Jie Zhao, Hongxing Li, Kai-Li He, Yibang Chen, Lloyd Mayer, Jay C. Unkeless, Huabao Xiong
Journal: Cancer Research (2005)

Abstract The signal pathways that trigger tumor cell escape from immune surveillance are incompletely understood. Toll-like receptors (TLRs), which activate innate and adaptive immune responses, are thought to be restricted to immune cells. We show here that TLRs, including TLR4, are expressed on tumor cells from a wide variety of tissues, suggesting that TLR activation may be an important event in tumor cell immune evasion. Activation of TLR4 signaling in tumor cells by lipopolysaccharide induces the synthesis of various soluble factors and proteins including interleukin-6, inducible nitric oxide synthase, interleukin-12, B7-H1, and B7-H2, and results in resistance of tumor cells to CTL attack. In addition, lipopolysaccharide-stimulated tumor cell supernatants inhibit both T cell proliferation and natural killer cell activity. Blockade of the TLR4 pathway by either TLR4 short interfering RNA or a cell-permeable TLR4 inhibitory peptide reverses tumor-mediated suppression of T cell proliferation and natural killer cell activity in vitro, and in vivo, delays tumor growth and thus prolongs the survival of tumor-bearing mice. These findings indicate that TLR signaling results in a cascade leading to tumor evasion from immune surveillance. These novel functions of TLRs in tumor biology suggest a new class of therapeutic targets for cancer therapy.
Combining progression-free survival and overall survival as a novel composite endpoint for glioblastoma trials
Authors: Lorenzo Trippa, Patrick Y. Wen, Giovanni Parmigiani, Donald A. Berry, Brian M. Alexander
Journal: Neuro-Oncology (2015)

The use of auxiliary endpoints may provide efficiencies for clinical trial design, but such endpoints may not have intrinsic clinical relevance or clear linkage to more meaningful endpoints. The purpose of this study was to generate a novel endpoint that considers both overall survival (OS) and earlier events such as progression-free survival (PFS) and determine whether such an endpoint could increase efficiency in the design of glioblastoma clinical trials.Recognizing that the association between PFS and OS varies depending on therapy and tumor type, we developed a statistical model to predict OS based on PFS as the trial progresses. We then evaluated the efficiency of our model using simulations of adaptively randomized trials incorporating PFS and OS distributions from prior published trials in neuro-oncology.When treatment effects on PFS and OS are concordant, our proposed approach results in efficiency gains compared with randomization based on OS alone while sacrificing minimal efficiency compared with using PFS as the primary endpoint. When treatment effects are limited to PFS, our approach provides randomization probabilities that are close to those based on OS alone.Use of OS as the primary endpoint, combined with statistical modeling of the relationship between OS and PFS during the course of the trial, results in more robust and efficient trial designs than using either endpoint alone.