tbuckley/cabot-search huggingface dataset:
Bioactive taxoids from the Japanese yew <i>Taxus cuspidata</i>
Authors: Jun'ichi Kobayashi, Hideyuki Shigemori
Journal: Medicinal Research Reviews (2002)

Abstract A series of new taxoids, named taxuspines A–H and J–Z ( 1 – 25 ) and taxezopidines A–H and J–L ( 26 – 36 ), have been isolated together with 37 known taxoids ( 37 – 73 ) including paclitaxel ( 53 ) from the Japanese yew, Taxus cuspidata Sieb. et Zucc. (Taxaceae). These new taxoids possess various skeletons containing 5/7/6, 6/10/6, 6/5/5/6, 6/8/6, or 6/12‐membered ring systems. Among the new taxoids, some non‐taxol‐type compounds remarkably reduced CaCl 2 ‐induced depolymerization of microtubules, or increased cellular accumulation of vincristine in multidrug‐resistant tumor cells as potent as verapamil. On the other hand, chemical derivatization of taxinine ( 37 ), one of major taxoids obtained from this yew, led to the discovery of unusual reactions of taxinine derivatives. Here we describe our recent results on the isolation, structure elucidation, and bioactivity of these new and known taxoids and the formation of unexpected products of the unusual reactions of taxinine. © 2002 Wiley Periodicals, Inc. Med Res Rev, 22, No. 3, 305–328, 2002; Published online in wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/med.10005
MAPK Activation Predicts Poor Outcome and the MEK Inhibitor, Selumetinib, Reverses Antiestrogen Resistance in ER-Positive High-Grade Serous Ovarian Cancer
Authors: Karina E. Hew, Philip C. Miller, Dorraya El-Ashry, Jun Sun, Alexandra H. Besser, Tan A. Ince, Mengnan Gu, Zhi Wei, Gao Zhang, Patricia Brafford, Wei Gao, Yiling Lu, Gordon B. Mills, Joyce M. Slingerland, Fiona Simpkins
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Although 67% of high-grade serous ovarian cancers (HGSOC) express the estrogen receptor (ER), most fail antiestrogen therapy. Because MAPK activation is frequent in ovarian cancer, we investigated if estrogen regulates MAPK and if MEK inhibition (MEKi) reverses antiestrogen resistance. Experimental Design: Effects of MEKi (selumetinib), antiestrogen (fulvestrant), or both were assayed in ER-positive HGSOC in vitro and in xenografts. Response biomarkers were investigated by gene expression microarray and reverse phase protein array (RPPA). Genes differentially expressed in two independent primary HGSOC datasets with high versus low pMAPK by RPPA were used to generate a “MAPK-activated gene signature.” Gene signature components that were reversed by MEKi were then identified. Results: High intratumor pMAPK independently predicts decreased survival (HR, 1.7; CI &amp;gt; 95%,1.3–2.2; P = 0.0009) in 408 HGSOC from The Cancer Genome Atlas. A differentially expressed “MAPK-activated” gene subset was also prognostic. “MAPK-activated genes” in HGSOC differ from those in breast cancer. Combined MEK and ER blockade showed greater antitumor effects in xenografts than monotherapy. Gene set enrichment analysis and RPPA showed that dual therapy downregulated DNA replication and cell-cycle drivers, and upregulated lysosomal gene sets. Selumetinib reversed expression of a subset of “MAPK-activated genes” in vitro and/or in xenografts. Three of these genes were prognostic for poor survival (P = 0.000265) and warrant testing as a signature predictive of MEKi response. Conclusions: High pMAPK is independently prognostic and may underlie antiestrogen failure. Data support further evaluation of fulvestrant and selumetinib in ER-positive HGSOC. The MAPK-activated HGSOC signature may help identify MEK inhibitor responsive tumors. Clin Cancer Res; 22(4); 935–47. ©2015 AACR.
A human memory T cell subset with stem cell–like properties
Authors: Luca Gattinoni, Enrico Lugli, Yun Ji, Zoltan Pos, Chrystal M Paulos, Máire F Quigley, Jorge R Almeida, Emma Gostick, Zhiya Yu, Carmine Carpenito, Ena Wang, Daniel C Douek, David A Price, Carl H June, Francesco M Marincola, Mario Roederer, Nicholas P Restifo
Journal: Nature Medicine (2011)
AKAP Mediated Signal Transduction
Authors: Jennifer J. Carlisle Michel, John D. Scott
Journal: The Annual Review of Pharmacology and Toxicology (2002)

Compartmentalization of cyclic AMP-dependent protein kinase (PKA) is achieved through association with A-kinase anchoring proteins (AKAPs). AKAPs are a group of structurally diverse proteins with the common function of binding to the regulatory subunit of PKA and confining the holoenzyme to discrete locations within the cell. This mode of regulation ensures that PKA is exposed to isolated cAMP gradients, which allows for efficient catalytic activation and accurate substrate selection. Several AKAPs coordinate multiple members of signaling cascades, effectively assembling upstream activators and downstream effectors within the same macromolecular complex. Consequently, AKAPs may serve as points of integration for numerous signaling pathways. This review details the most recent advances in our understanding of the various biological functions dependent upon AKAP-anchored signaling complexes.
The Human Agonistic CD40 Antibody ADC-1013 Eradicates Bladder Tumors and Generates T-cell–Dependent Tumor Immunity
Authors: Sara M. Mangsbo, Sissela Broos, Erika Fletcher, Niina Veitonmäki, Christina Furebring, Eva Dahlén, Per Norlén, Malin Lindstedt, Thomas H. Tötterman, Peter Ellmark
Journal: Clinical Cancer Research (2014)

Local administration of immune-activating antibodies may increase the efficacy and reduce the immune-related adverse events associated with systemic immunotherapy of cancer. Here, we report the development and affinity maturation of a fully human agonistic CD40 antibody (IgG1), ADC-1013.We have used molecular engineering to generate an agonistic antibody with high affinity for CD40. The functional activity of ADC-1013 was investigated in human and murine in vitro models. The in vivo effect was investigated in two separate bladder cancer models, both using human xenograft tumors in immune deficient NSG mice and using a syngeneic bladder cancer model in a novel human CD40 transgenic mouse.Activation of dendritic cells (DC) by ADC-1013 results in upregulation of the costimulatory molecules CD80 and CD86, and secretion of IL12. ADC-1013 also activates DCs from human CD40 transgenic mice, and peptide-pulsed and ADC-1013-stimulated DCs induce antigen-specific T-cell proliferation in vitro. In vivo, treatment with ADC-1013 in a syngeneic bladder cancer model, negative for hCD40, induces significant antitumor effects and long-term tumor-specific immunity. Furthermore, ADC-1013 demonstrates significant antitumor effects in a human bladder cancer transplanted into immunodeficient NSG mice.Our data demonstrate that ADC-1013 induces long-lasting antitumor responses and immunologic memory mediated by CD40 stimulation. To the best of our knowledge, ADC-1013 represents the first immunomodulatory antibody developed for local immunotherapy of cancer.
Protection of human left ventricular myocardium from cutting injury with 2,3-butanedione monoxime.
Authors: L A Mulieri, G Hasenfuss, F Ittleman, E M Blanchard, N R Alpert
Journal: Circulation Research (1989)

To prevent dissection injury when cutting strip preparations from human left ventricular papillary muscle tissue, dissections were carried out with 2,3-butanedione monoxime (30 mM) added to Krebs-Ringer solution and followed by washout with normal solution. Eleven muscle strip preparations were dissected from left ventricular papillary muscle tissue of five patients undergoing mitral valve replacement surgery. The average muscle strip length was 6.8 +/- 1.4 mm, and cross-section area was 0.49 +/- 0.16 mm2. Peak twitch tension was 2.02 +/- 1.33 g/mm2 and ranged from 0.67 to 5.5 g/mm2 at an extracellular calcium concentration of 2.5 mM (21 degrees C, 0.16 Hz). In one muscle strip, which was stored in Krebs-Ringer plus 2,3-butanedione monoxime solution for 20 hours, peak twitch tension in normal Krebs-Ringer solution was 1.85 g/mm2. When temperature was increased from 21 degrees C, there was a continuous increase in peak twitch tension (by 38%) up to about 28 degrees C; then peak twitch tension decreased so that at 37 degrees C (n = 3) average peak twitch tension was lower than at 21 degrees C by 47%. The force-frequency relation exhibited a broad force plateau between 40 and 120 beats/min at 37 degrees C. The plateau was markedly narrowed at 30 degrees C and 24 degrees C. Thermopile heat measurements revealed appropriate waveform characteristics in high-resolution single-beat heat records indicating minimal surface cell damage. Thus, cardioplegia with 2,3-butanedione monoxime protects human left ventricular myocardium from dissection injury facilitating dissection and preservation of strip preparations with extraordinarily low cross-sectional areas and high peak twitch tensions. These preparations are suitable for myothermal and mechanical measurements.
Reproducibility of Results obtained with Indicator-Dilution Technique for Estimating Cardiac Output in Man
Authors: Julian C. Sleeper, Howard K. Thompson, Henry D. McIntosh, Robert C. Elston
Journal: Circulation Research (1962)

The reproducibility of the indicator-dilution estimation of cardiac output was assessed by evaluating pairs of indicator-dilution curves recorded simultaneously from normal subjects and patients by two similar linear densitometers. Measurement error was defined by comparison of 90 simultaneous measurements obtained from the same needle; two standard deviations of the difference equaled 430 ml./min. (6 per cent of the mean cardiac output). A much larger variation resulted when 159 simultaneous cardiac output determinations, sampling from the brachial and femoral arteries, were compared (two standard deviations of the difference equaled 1,200 ml./min. or 20 per cent of the mean cardiac output). Intermediate values were obtained in a comparison of 29 simultaneous measurements from the radial and brachial arteries of the same arm. The larger deviations between the simultaneous measurements from different arteries suggested nonuniform distribution of dye. The discrepancies between the paired cardiac output determinations were larger and more frequent when peripheral blood flow alterations were produced. However, the nature of dye-distribution abnormalities and the mechanisms whereby peripheral arterial flow influence the dye-dilution cardiac output measurement were not evident.
Lost in transdifferentiation
Authors: Mark H. Hoofnagle, Brian R. Wamhoff, Gary K. Owens
Journal: Journal of Clinical Investigation (2004)

What are the true origins of the smooth muscle cells (SMCs) present in the intimal lesions of transplant arteriosclerosis? A new study in the JCI shows that Sca-1+ cells purified from the mouse aortic root can migrate through an irradiated vein graft to the neointima of the vessel and transdifferentiate to express the early SMC differentiation marker gene SM22. Do Sca-1+ cells transdifferentiate into SMC-like cells, or is activation of SMC marker genes a consequence of fusion of these cells with preexisting SMCs, a possibility raised by results of studies of adult stem cells in animal models of liver regeneration ? Or could this be bona fide transdifferentiation that recapitulates the pathologic processes in humans?
Prediction of Panic Response to a Respiratory Stimulant by Reduced Orbitofrontal Cerebral Blood Flow in Panic Disorder
Authors: Justine M. Kent, Jeremy D. Coplan, Osama Mawlawi, Jose M. Martinez, Susan T. Browne, Mark Slifstein, Diana Martinez, Anissa Abi-Dargham, Marc Laruelle, Jack M. Gorman
Journal: American Journal of Psychiatry (2005)

Lack of appropriate top-down governance by frontal cortical regions over a hypersensitive amygdala-centered fear neurocircuitry has been hypothesized to be central in the pathophysiology of panic disorder. The aim of this study was to examine regional cerebral blood flow changes in response to anxiety/panic provocation in subjects with panic disorder and healthy comparison subjects.Quantitative water method positron emission tomography was used to obtain brain images of five untreated subjects with panic disorder and five healthy comparison subjects before and during anxiogenic challenge with intravenous doxapram, an acute respiratory stimulant.Baseline perfusion of the orbitofrontal cortex predicted panic attacks: lower perfusion was associated with heightened anxiety in response to doxapram challenge.The orbitofrontal cortex may be important in the regulation of responding to fear and is a potential area of aberrant functioning in panic disorder.
Frequency and Timing of Severe Hypoglycemia Affects Spatial Memory in Children With Type 1 Diabetes
Authors: Tamara Hershey, Dana C. Perantie, Stacie L. Warren, Emily C. Zimmerman, Michelle Sadler, Neil H. White
Journal: Diabetes Care (2005)

OBJECTIVE—Repeated severe hypoglycemia has been reported to reduce long-term spatial memory in children with type 1 diabetes. Early exposure to hypoglycemia may be more damaging to cognitive function than later exposure. Our goal was to determine whether the age at which severe hypoglycemia occurs modulates the impact of severe hypoglycemia frequency on long-term spatial memory. RESEARCH DESIGN AND METHODS—We combined data from three independent studies to obtain a sample of children aged 6–18 years with type 1 diabetes (n = 103) and nondiabetic control subjects (n = 60). Each study evaluated previous severe hypoglycemia and tested short (5 s)- and long (60 s)-delay spatial memory with the spatial delayed response task. Type 1 diabetic participants were categorized as having zero, one to two, or three or more severe hypoglycemic episodes and as having their first severe hypoglycemic episode before or after 5 years of age. Information on chronic hyperglycemia (HbA1c values) was also collected. RESULTS—We found that repeated severe hypoglycemia (more than three episodes) reduced long-delay spatial delayed response performance, particularly when severe hypoglycemic episodes began before the age of 5 years. Age of type 1 diabetes onset and estimates of chronic hyperglycemia did not influence performance. CONCLUSIONS—High frequency of and early exposure to severe hypoglycemia during development negatively affects spatial long-term memory performance.
Clinical patterns of familial inflammatory bowel disease.
Authors: J Satsangi, C Grootscholten, H Holt, D P Jewell
Journal: Gut (1996)

BACKGROUND--Although many recent studies have shown the increased risk of inflammatory bowel disease in relatives of patients with Crohn9s disease and ulcerative colitis, clinical patterns of disease within families remain relatively poorly documented. AIMS--In this study, clinical characteristics (disease type, extent, age on onset, need for surgery, and presence of extraintestinal manifestations) have been compared in affected subjects in multiply-affected families, with inflammatory bowel disease. METHODS--54 families in whom one parent and at least one child were affected (a total of 77 parent-child pairs) and 155 families in whom at least two siblings were affected (a total of 190 affected sibling pairs) were involved. RESULTS--In affected parent-child pairs, parent and child were concordant for disease type in 58 of 77 pairs (75.3%), for extent in 63.6%, extraintestinal manifestations in 70.1%, and smoking history in 85%. The median age of onset in parents was significantly higher than offspring (p &lt; 0.0001). In 40 pairs, 60.6%, the parent was at least 10 years older than child. Siblings were concordant for disease type in 81.6% of the affected sibling pairs, extent in 76.0%, extraintestinal manifestations in 83.8%, and smoking history in 81.3%. In contrast with the parent-child pairs, 68.1% (111 sibling pairs) siblings were diagnosed within 10 years of each other. The median age of onset was 24.0 years. CONCLUSIONS--This study has shown consistent clinical patterns in many families with inflammatory bowel disease. The differences in age of onset between parents and children are not readily explained by a simple cohort effect or ascertainment bias, and may reflect effects of genetic factors, producing anticipation between generations.
Atrial fibrillation and atrial vulnerability in patients with Brugada syndrome
Authors: Hiroshi Morita, Kengo Kusano-Fukushima, Satoshi Nagase, Yoshihisa Fujimoto, Kenichi Hisamatsu, Hideki Fujio, Kayo Haraoka, Makoto Kobayashi, Shiho Takenaka Morita, Kazufumi Nakamura, Tetsuro Emori, Hiromi Matsubara, Kazumasa Hina, Toshimasa Kita, Masahiko Fukatani, Tohru Ohe
Journal: Journal of the American College of Cardiology (2002)
Intermittent chemotherapy plus either intermittent or continuous cetuximab for first-line treatment of patients with KRAS wild-type advanced colorectal cancer (COIN-B): a randomised phase 2 trial
Authors: Harpreet Wasan, Angela M Meade, Richard Adams, Richard Wilson, Cheryl Pugh, David Fisher, Benjamin Sydes, Ayman Madi, Bruce Sizer, Charles Lowdell, Gary Middleton, Rachel Butler, Richard Kaplan, Tim Maughan
Journal: The Lancet Oncology (2014)

Advanced colorectal cancer is treated with a combination of cytotoxic drugs and targeted treatments. However, how best to minimise the time spent taking cytotoxic drugs and whether molecular selection can refine this further is unknown. The primary aim of this study was to establish how cetuximab might be safely and effectively added to intermittent chemotherapy.
Launching a New Food Product or Dietary Supplement in the United States: Industrial, Regulatory, and Nutritional Considerations
Authors: John Weldon Finley, John Wescott Finley, Kathleen Ellwood, James Hoadley
Journal: Annual Review of Nutrition (2014)

Launching a new food/dietary supplement into the US market can be a confusing process to those unfamiliar with the food industry. Industry capability and product specifications are initial determinants of whether a candidate product can be manufactured in a reproducible manner and whether pilot production can be brought up to the market scale. Regulatory issues determine how a product can be produced and marketed; the primary federal institutions involved in regulations are the US Department of Agriculture, the Food and Drug Administration, and the Federal Trade Commission. A primary distinction is made between food and drugs, and no product may enter the food market if it is in part or whole a drug. Product safety is a major concern, and myriad regulations govern the determination of safety. New foods/dietary supplements are often marketed by health claims or structure/function claims, and there are specific regulations pertaining to claims. Not understanding the regulatory issues involved in developing a new product or failing to comply with associated regulations can have legal and financial repercussions.
An important virus in asthma pathophysiology?
Authors: D Waine
Journal: Thorax (2006)

▴ Pifferi M, Maggi F, Andreoli E, et al . Associations between nasal torquetenovirus load and spirometric indices in children with asthma. J Infect Dis2005;192:1141–8 [OpenUrl][1][Abstract/FREE Full Text][2] There is evidence that viral respiratory infections may have an important role in asthma. Torquetenovirus (TTV) is widespread in the general population, and increased loads have been associated with decreased circulating CD3 and CD4 cells as well as increased circulating B cells and eosinophilic cationic protein (ECP), suggesting possible immunomodulatory effects. This group investigated, for … [1]: {openurl}?query=rft.jtitle%253DJ%2BInfect%2BDis%26rft_id%253Dinfo%253Adoi%252F10.1086%252F444389%26rft_id%253Dinfo%253Apmid%252F16136454%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/ijlink?linkType=ABST&journalCode=jinfdis&resid=192/7/1141&atom=%2Fthoraxjnl%2F61%2F2%2F154.atom
Efficacy, Biodistribution, and Pharmacokinetics of CD22-Targeted Pegylated Liposomal Doxorubicin in a B-cell Non–Hodgkin's Lymphoma Xenograft Mouse Model
Authors: Joseph M. Tuscano, Shiloh M. Martin, Yunpeng Ma, William Zamboni, Robert T. O'Donnell
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Non–Hodgkin's lymphoma (NHL) is the sixth most common cause of cancer death in the U.S. Pegylated liposomal doxorubicin (PLD) is a liposomal form of doxorubicin (DXR) that causes less toxicity than does free DXR. To further enhance efficacy and decrease toxicity, we conjugated HB22.7, an anti-CD22 monoclonal antibody to PLD, thus creating CD22-targeted immunoliposomal PLD (IL-PLD). Experimental Design: In vitro cytotoxicity of IL-PLD and PLD was assessed in CD22-positive and CD22-negative cell lines. Biodistribution, myelotoxicity, and plasma pharmacokinetics were measured in NHL xenograft–bearing mice treated with IL-PLD or PLD. Survival, tumor volume, and toxicity (WBC counts, body weights) were assessed in mice receiving a single dose (8, 12, or 16 mg DXR/kg) or three doses (8 mg DXR/kg/dose) of IL-PLD; controls were PLD, free DXR, PLD plus unconjugated HB22.7, IL-null (HB22.7-conjugated empty liposome), and nontreated mice. Results: IL-PLD improved cytotoxicity over PLD only in CD22-positive cells. IL-PLD displayed similar pharmacokinetics and toxicities as PLD. Tumor DXR accumulation was greater and tumor/normal tissue ratios were similar (spleen) or greater (kidney, lung, and liver) in mice treated with IL-PLD versus PLD. IL-PLD reduced tumor volume more effectively than PLD at all doses; the three-dose regimen was superior. The three-dose regimen was used in confirmatory studies, which showed that IL-PLD produced significantly greater tumor volume reduction and enhanced survival versus PLD. Conclusion: IL-PLD has increased efficacy without increased toxicity compared with PLD. This suggests that IL-PLD may be an improved form of DXR-based therapy of NHL. Clin Cancer Res; 16(10); 2760–8. ©2010 AACR.
Human malignant T cells capable of inducing an immunoglobulin class switch.
Authors: L Mayer, D N Posnett, H G Kunkel
Journal: The Journal of Experimental Medicine (1985)

Evidence is presented for the existence of a "switch" T cell derived from a patient with mycosis fungoides/Sezary's syndrome. The serum immunoglobulin profile in this patient revealed high IgG and IgA but no detectable IgM. Peripheral blood mononuclear cells from this patient secreted only IgG and IgA in the presence of pokeweed mitogen. T cells (Trac) co-cultured with normal allogeneic non-T cells and pokeweed mitogen resulted in only IgG and IgA PFC, with little or no IgM secretion. There was no evidence of active suppression of IgM. Rather, these T cells appeared to induce an Ig class switch from IgM to IgG and IgA, when co-cultured with mu+ tonsillar B cells. Further evidence was obtained using mononuclear cells derived from a patient with immunodeficiency and hyper-IgM, a syndrome characterized by a lack of IgG and IgA secretion. The addition of Trac cells to either peripheral blood mononuclear cells or non-T cells from a patient with hyper-IgM syndrome resulted in new secretion of IgG, with a concomitant decrease in IgM secretion, whereas control T cells were not effective in inducing secretion of any isotype other than IgM. Isolated Tac+ T cells from Trac appear to be responsible for this effect.