tbuckley/cabot-search huggingface dataset:
Identification of a promising PI3K inhibitor for the treatment of multiple myeloma through the structural optimization
Authors: Kunkun Han, Xin Xu, Guodong Chen, Yuanying Zeng, Jingyu Zhu, Xiaolin Du, Zubin Zhang, Biyin Cao, Zhaopeng Liu, Xinliang Mao
Journal: Journal of Hematology & Oncology (2014)

We previously reported a PI3K inhibitor S14161 which displays a promising preclinical activity against multiple myeloma (MM) and leukemia, but the chiral structure and poor solubility prevent its further application. Six S14161 analogs were designed based on the structure–activity relationship; activity of the compounds in terms of cell death and inhibition of PI3K were analyzed by flow cytometry and Western blotting, respectively; anti-myeloma activity in vivo was performed on two independent xenograft models. Among the six analogs, BENC-511 was one of the most potent compounds which significantly inhibited PI3K activity and induced MM cell apoptosis. BENC-511 was able to inactivate PI3K and its downstream signals AKT, mTOR, p70S6K, and 4E-BP1 at 1 μM but had no effects on their total protein expression. Consistent with its effects on PI3K activity, BENC-511 induced MM cell apoptosis which was evidenced by the cleavage of Caspase-3 and PARP. Notably, addition of insulin-like growth factor 1 and interleukin-6, two important triggers for PI3K activation in MM cells, partly blocked BENC-511-induced MM cell death, which further demonstrated that PI3K signaling pathway was critical for the anti-myeloma activity of BENC-511. Moreover, BENC-511 also showed potent oral activity against myeloma in vivo. Oral administration of BENC-511 decreased tumor growth up to 80% within 3 weeks in two independent MM xenograft models at a dose of 50 mg/kg body weight, but presented minimal toxicity. Suppression of BENC-511 on MM tumor growth was associated with decreased PI3K/AKT activity and increased cell apoptosis. Because of its potent anti-MM activity, low toxicity (LD50 oral >1.5 g/kg), and easy synthesis, BENC-511 could be developed as a promising agent for the treatment of MM via suppressing the PI3K/AKT signaling pathway.
Hyperglycemia Is Associated With Enhanced Thrombin Formation, Platelet Activation, and Fibrin Clot Resistance to Lysis in Patients With Acute Coronary Syndrome
Authors: Anetta Undas, Ilona Wiek, Ewa Stêpień, Krzysztof Zmudka, Wiesława Tracz
Journal: Diabetes Care (2008)

OBJECTIVE—Acute hyperglycemia on admission for acute coronary syndrome worsens the prognosis in patients with and without known diabetes. Postulated mechanisms of this observation include prothrombotic effects. The aim of this study was to evaluate the effect of elevated glucose levels on blood clotting in acute coronary syndrome patients. RESEARCH DESIGN AND METHODS—We studied 60 acute coronary syndrome patients within the first 12 h after pain onset, including 20 subjects with type 2 diabetes, 20 subjects with no diagnosed diabetes but with glucose levels &amp;gt;7.0 mmol/l, and 20 subjects with glucose levels &amp;lt;7.0 mmol/l. We determined generation of thrombin-antithrombin complexes (TATs) and soluble CD40 ligand (sCD40L), a platelet activation marker, at the site of microvascular injury, together with ex vivo plasma fibrin clot permeability and lysis time. RESULTS—The acute coronary syndrome patients with no prior diabetes but elevated glucose levels had increased maximum rates of formation and total production of TATs (by 42.9%, P &amp;lt; 0.0001, and by 25%, P &amp;lt; 0.0001, respectively) as well as sCD40L release (by 16.2%, P = 0.0011, and by 16.3%, P &amp;lt; 0.0001, respectively) compared with those with normoglycemia, whereas diabetic patients had the highest values of TATs and sCD40L variables (P &amp;lt; 0.0001 for all comparisons). Patients with hyperglycemia, with no previously diagnosed diabetes, had longer clot lysis time (by ∼18%, P &amp;lt; 0.0001) similar to that in diabetic subjects, but not lower clot permeability compared with that in normoglycemic subjects. CONCLUSIONS—Hyperglycemia in acute coronary syndrome is associated with enhanced local thrombin generation and platelet activation, as well as unfavorably altered clot features in patients with and without a previous history of diabetes.
Gastrointestinal Cancers: Epidemiological, Clinical, Histological and Therapeutic Characteristic (210 Cases Treated in the Radiotherapy Department of University Hospital of Hassan II-FES-Morocco Between January 2012 and December 2013)
Authors: Farhane Fatima Zahra, Loikili Kaoutar, Alami Zineb, Masbah Ouafae, Bouhafa Touria, Elmazghi Abderrahmane, Hassouni Khalid
Journal: Annals of Oncology (2014)
17β-Estradiol Induces Down-Regulation of <i>Cap43/NDRG1/Drg-1</i>, a Putative Differentiation-Related and Metastasis Suppressor Gene, in Human Breast Cancer Cells
Authors: Abbas Fotovati, Teruhiko Fujii, Miki Yamaguchi, Masayoshi Kage, Kazuo Shirouzu, Shinji Oie, Yuji Basaki, Mayumi Ono, Hideaki Yamana, Michihiko Kuwano
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Cap43 is known as a nickel- and calcium-inducible gene. In the present study, we examined whether 17β-estradiol (E2) could affect the expression of Cap43 in breast cancer. Experimental Design: Real-time PCR, immunoblotting, and immunocytochemistry were used to examine the expression of Cap43 and estrogen receptor-α (ER-α) in breast cancer cell lines. MDA-MB-231 and SK-BR-3 cell lines were transfected with ER-α cDNA to establish cells overexpressing ER-α. Immunohistochemistry was used to evaluate the expression of the Cap43 protein in breast cancer patients (n = 96), and the relationship between Cap43 expression and clinicopathologic findings was examined. Results: Of the eight cell lines, four expressed higher levels of Cap43 with very low levels of ER-α, whereas the other four expressed lower levels of Cap43 with high ER-α levels. Treatment with E2 decreased the expression of Cap43 dose-dependently in ER-α-positive cell lines but not in ER-α-negative lines. Administration of antiestrogens, tamoxifen and ICI 182780, abrogated the E2-induced down-regulation of Cap43. Overexpression of ER-α in both ER-α-negative cell lines, SK-BR-3 and MDA-MB-231, resulted in down-regulation of Cap43. Immunostaining studies showed a significant correlation between Cap43 expression and the histologic grade of tumors (P = 0.0387). Furthermore, Cap43 expression was inversely correlated with the expression of ER-α (P = 0.0374). Conclusions: E2-induced down-regulation of Cap43 seems to be mediated through ER-α-dependent pathways in breast cancer cells both in culture and in patients. Cap43 has potential as a molecular marker to determine the therapeutic efficacy of antiestrogenic anticancer agents in breast cancer.
Scientific rationale for using a single inhaler for asthma control
Authors: P. J. Barnes
Journal: European Respiratory Journal (2007)

Clinical trials have recently demonstrated that using a budesonide/formoterol combination inhaler as regular maintenance treatment twice daily but also as a rescue therapy for breakthrough symptoms can provide more effective control of asthma, particularly in reducing exacerbations, than using a short-acting beta2-agonist or formoterol as rescue therapy. This suggests that the corticosteroid component of the combination therapy plays an important role in rescue therapy. Formoterol as a rescue therapy is effective in relieving symptoms by relaxing airway smooth muscle but is also likely to have important inhibitory effects on mast cells, plasma exudation and neutrophilic inflammation. Inhaled corticosteroids have much more rapid suppressing effects on airway inflammation than previously recognised and the increased dose used as rescue therapy may prevent the increase in airway inflammation that occurs during the evolution of an exacerbation, thus preventing its development. It is likely that the molecular interactions between beta2-agonists and corticosteroids also enhance the effect of the combination therapy as rescue therapy. There is now a strong scientific rationale for single inhaler therapy in asthma, but more research is now needed to better understand the mechanisms involved.
Weekly therapy with folinic acid (FA) and high-dose 5-fluorouracil (5-FU) 24-hour infusion in pretreated patients with metastatic colorectal carcinoma
Authors: H.J. Weh, H.J. Wilke, J. Dierlamm, U. Klaassen, R. Siegmund, H.J. Illiger, A. Schalhorn, E.D. Kreuser, U. Hilgenfeld, B. Steinke, W. Weber, O. Burkhard, A. Zoller, J. Pfitzner, R. Subert, R. Kriebel, D.K. Hossfeld
Journal: Annals of Oncology (1994)
MAKING BRAIN CONNECTIONS: Neuroanatomy and the Work of TPS Powell, 1923–1996
Authors: Edward G. Jones
Journal: Annual Review of Neuroscience (1999)

▪ Abstract Dr. Thomas PS Powell was one of the founders of modern neuroanatomy. His career spanned an era that saw techniques for analyzing connections in the central nervous system dramatically increase in number and resolving power. In tracing the history of his research, one can see how the introduction of each new technique provided an incremental step in analytical capacity although eventually revealing its own limitations. Also evident is the extent to which prejudices born in the days of applying earlier techniques could continue to influence the interpretation of results obtained with new ones. Powell's contributions to neuroscience were extremely wide-ranging, encompassing investigations of the circuitry of the basal ganglia, corticofugal connections, topographic maps in sensory systems, central olfactory pathways, corticocortical and commissural connections, and pathways for sensory convergence in the cerebral cortex. From these investigations, made with tract tracing techniques, much existing knowledge of forebrain organization is derived. He was also one of the earliest investigators to use electron microscopy in the investigation of the central nervous system, and his electron microscopic studies on the olfactory bulb, thalamus, cerebral cortex, and basal ganglia laid, to a large extent, the foundations for all modern research on the synaptic circuitry of these structures. He was given to synthesizing data across systems in order to arrive at common principles of brain organization. A number of these syntheses have been sources of great interest and, occasionally, controversy.
A Phase I Study of a Combination of Yttrium-90–Labeled Anti–Carcinoembryonic Antigen (CEA) Antibody and Gemcitabine in Patients with CEA-Producing Advanced Malignancies
Authors: Stephen Shibata, Andrew Raubitschek, Lucille Leong, Marianna Koczywas, Lawrence Williams, Jiping Zhan, Jeffrey Y.C. Wong
Journal: Clinical Cancer Research (2009)

Abstract Purpose: To determine the maximum tolerated dose of combined therapy using an yttrium-90–labeled anti–carcinoembryonic antigen (CEA) antibody with gemcitabine in patients with advanced CEA-producing solid tumors. Experimental Design: The chimeric human/murine cT84.66 is an anti-CEA intact IgG1, with high affinity and specificity to CEA. This was given at a fixed yttrium-90–labeled dose of 16.6 mCi/m2 to subjects who had and an elevated CEA in serum or in tumor by immunohistochemistry. Also required was a tumor that imaged with an 111In-labeled cT84.66 antibody. Patients were treated with escalating doses of gemcitabine given i.v. over 30 minutes on day 1 and 3 after the infusion of the yttrium-90–labeled antibody. Patients were treated in cohorts of 3. The maximum tolerated dose was determined as the highest level at which no &amp;gt;1 of 6 patients experienced a dose limiting toxicity. Results: A total of 36 patients were enrolled, and all but one had prior systemic therapy. The maximum tolerated dose of gemcitabine in this combination was 150 mg/m2. Dose limiting toxicities at a gemcitabine dose of 165 mg/m2 included a grade 3 rash and grade 4 neutropenia. One partial response was seen in a patient with colorectal cancer, and 4 patients had a &amp;gt;50% decrease in baseline CEA levels associated with stable disease. Human antichimeric antibody responses were the primary reason for stopping treatment in 12 patients. Conclusions: Feasibility of combining gemcitabine with an yttrium-90–labeled anti-CEA antibody is shown with preliminary evidence of clinical response.
The tissue distribution of the B7-2 costimulator in mice: abundant expression on dendritic cells in situ and during maturation in vitro.
Authors: K Inaba, M Witmer-Pack, M Inaba, K S Hathcock, H Sakuta, M Azuma, H Yagita, K Okumura, P S Linsley, S Ikehara, S Muramatsu, R J Hodes, R M Steinman
Journal: The Journal of Experimental Medicine (1994)

B7-2 is a recently discovered, second ligand for the CTLA-4/CD28, T cell signaling system. Using the GL-1 rat monoclonal antibody (mAb), we monitored expression of B7-2 on mouse leukocytes with an emphasis on dendritic cells. By cytofluorography, little or no B7-2 was detected on most cell types isolated from spleen, thymus, peritoneal cavity, skin, marrow, and blood. However, expression of B7-2 could be upregulated in culture. In the case of epidermal and spleen dendritic cells, which become highly immunostimulatory for T cells during a short period of culture, the upregulation of B7-2 was dramatic and did not require added stimuli. Lipopolysaccharide did not upregulate B7-2 levels on dendritic cells, in contrast to macrophages and B cells. By indirect immunolabeling, the level of staining with GL-1 mAb exceeded that seen with rat mAbs to several other surface molecules including intercellular adhesion molecule 1, B7-1, CD44, and CD45, as well as new hamster mAbs to CD40, CD48, and B7-1/CD80. Of these accessory molecules, B7-2 was a major species that increased in culture, implying a key role for B7-2 in the functional maturation of dendritic cells. B7-2 was the main (&amp;gt; 90%) CTLA-4 ligand on mouse dendritic cells. When we applied GL-1 to tissue sections of a dozen different organs, clear-cut staining with B7-2 antigen was found in many. B7-2 staining was noted on liver Kupffer cells, interstitial cells of heart and lung, and profiles in the submucosa of the esophagus. B7-2 staining was minimal in the kidney and in the nonlymphoid regions of the gut, and was not observed at all in the brain. In the tongue, only rare dendritic cells in the oral epithelium were B7-2+, but reactive cells were scattered about the interstitial spaces of the muscle. In all lymphoid tissues, Gl-1 strongly stained certain distinct regions that are occupied by dendritic cells and by macrophages. For dendritic cells, these include the thymic medulla, splenic periarterial sheaths, and lymph node deep cortex; for macrophages, the B7-2-rich regions included the splenic marginal zone and lymph node subcapsular cortex. Splenic B7-2+ cells were accessible to labeling with GL-1 mAb given intravenously. Dendritic cell stimulation of T cells (DNA synthesis) during the mixed leukocyte reaction was significantly (35-65%) blocked by GL-1.(ABSTRACT TRUNCATED AT 400 WORDS)
A simple metric of promoter architecture robustly predicts expression breadth of human genes suggesting that most transcription factors are positive regulators
Authors: Laurence D Hurst, Oxana Sachenkova, Carsten Daub, Alistair RR Forrest, Lukasz Huminiecki
Journal: Genome biology (2014)

Conventional wisdom holds that, owing to the dominance of features such as chromatin level control, the expression of a gene cannot be readily predicted from knowledge of promoter architecture. This is reflected, for example, in a weak or absent correlation between promoter divergence and expression divergence between paralogs. However, an inability to predict may reflect an inability to accurately measure or employment of the wrong parameters. Here we address this issue through integration of two exceptional resources: ENCODE data on transcription factor binding and the FANTOM5 high-resolution expression atlas. Consistent with the notion that in eukaryotes most transcription factors are activating, the number of transcription factors binding a promoter is a strong predictor of expression breadth. In addition, evolutionarily young duplicates have fewer transcription factor binders and narrower expression. Nonetheless, we find several binders and cooperative sets that are disproportionately associated with broad expression, indicating that models more complex than simple correlations should hold more predictive power. Indeed, a machine learning approach improves fit to the data compared with a simple correlation. Machine learning could at best moderately predict tissue of expression of tissue specific genes. We find robust evidence that some expression parameters and paralog expression divergence are strongly predictable with knowledge of transcription factor binding repertoire. While some cooperative complexes can be identified, consistent with the notion that most eukaryotic transcription factors are activating, a simple predictor, the number of binding transcription factors found on a promoter, is a robust predictor of expression breadth.
Clinical significance of CD38 expression in chronic lymphocytic leukemia
Authors: Giovanni Del Poeta, Luca Maurillo, Adriano Venditti, Francesco Buccisano, Anna Maria Epiceno, Giovanni Capelli, Anna Tamburini, Giovanna Suppo, Alessandra Battaglia, Maria Ilaria Del Principe, Beatrice Del Moro, Mario Masi, Sergio Amadori
Journal: Blood (2001)
Host and Direct Antitumor Effects and Profound Reduction in Tumor Metastasis with Selective EP4 Receptor Antagonism
Authors: Li Yang, Yuhui Huang, Rut Porta, Kiyoshi Yanagisawa, Adriana Gonzalez, Eric Segi, David H. Johnson, Shuh Narumiya, David P. Carbone
Journal: Cancer Research (2006)

Abstract Prostaglandin E2 (PGE2), one of the major metabolites of cyclooxygenase-2, has been implicated in tumorigenesis and tumor progression in several human cancers, including colorectal and lung. Here, we show that one of the PGE2 receptors, the EP4 receptor, plays an important role in metastasis in both of these tumor types. Using i.v. injected Lewis lung carcinoma (3LL), we found that tumor metastasis to lung was significantly reduced when mice were treated with a specific EP4 antagonist ONO-AE3-208 or when EP4 receptor expression was knocked down in the tumor cells using RNA interference technology. Host EP4 receptors also contributed to tumor metastasis and tumor growth with decreased metastasis and tumor growth observed in EP4 receptor knockout animals. In vitro tumor cell adhesion, motility, invasion, colony formation, and Akt phosphorylation were all significantly inhibited when 3LL cells were treated with the EP4 receptor–specific antagonist. When the cells were treated with an EP4-specific agonist (AE1-734), we observed a worsening of these same features in vitro. Treatment with ONO-AE3-208 also profoundly decreased liver metastases after intrasplenic injection of MC26 colon cancer cells. Our data show that selective antagonism of EP4 receptor signaling results in a profound reduction in lung and colon cancer metastasis. Selective antagonism of the EP4 receptor may thus represent a novel therapeutic approach for the treatment of cancer and especially its propensity to metastasize. (Cancer Res 2006; 66(19): 9665-72)
Breast Cancer Prevention Using Calcium and Vitamin D: A Bright Future?
Authors: Corey Speers, Powel Brown
Journal: JNCI Journal of the National Cancer Institute (2008)

Despite aggressive treatment and screening efforts, breast cancer remains the second leading cause of cancer-related deaths among women in the United States (1). Because of the large number of women dying from this disease and the toxicity of breast cancer treatments, recent efforts have focused on identifying effective cancer preventive agents. These efforts have led to the development of antiestrogen agents, such as tamoxifen and raloxifene, which prevent approximately 50% of invasive breast cancers in women who are at high risk for breast cancer. However, the use of these agents for breast cancer prevention has been limited by their toxicity.
Glucose Variability; Does It Matter?
Authors: Sarah E. Siegelaar, Frits Holleman, Joost B. L. Hoekstra, J. Hans DeVries
Journal: Endocrine Reviews (2010)

Overall lowering of glucose is of pivotal importance in the treatment of diabetes, with proven beneficial effects on microvascular and macrovascular outcomes. Still, patients with similar glycosylated hemoglobin levels and mean glucose values can have markedly different daily glucose excursions. The role of this glucose variability in pathophysiological pathways is the subject of debate. It is strongly related to oxidative stress in in vitro, animal, and human studies in an experimental setting. However, in real-life human studies including type 1 and type 2 diabetes patients, there is neither a reproducible relation with oxidative stress nor a correlation between short-term glucose variability and retinopathy, nephropathy, or neuropathy. On the other hand, there is some evidence that long-term glycemic variability might be related to microvascular complications in type 1 and type 2 diabetes. Regarding mortality, a convincing relationship with short-term glucose variability has only been demonstrated in nondiabetic, critically ill patients. Also, glucose variability may have a role in the prediction of severe hypoglycemia. In this review, we first provide an overview of the various methods to measure glucose variability. Second, we review current literature regarding glucose variability and its relation to oxidative stress, long-term diabetic complications, and hypoglycemia. Finally, we make recommendations on whether and how to target glucose variability, concluding that at present we lack both the compelling evidence and the means to target glucose variability separately from all efforts to lower mean glucose while avoiding hypoglycemia.
Cytisine, the world's oldest smoking cessation aid
Authors: J. J. Prochaska, S. Das, N. L. Benowitz
Journal: BMJ (2013)

Growing evidence for its use as an affordable treatment globally 

Nearly 50 years ago, and before any smoking cessation aids were approved in the Western world, cytisine was being used in eastern and central Europe to help people quit smoking. An alkaloid with high affinity for the α4β2 nicotinic acetylcholine receptor subtype, cytisine is derived from the plant Cytisus laburnum . It was discovered in 1818, first isolated in 1865,1 and its actions were documented as “qualitatively indistinguishable from that of nicotine” in 1912.2 It was smoked as an accessible and cheap tobacco substitute by German and Russian soldiers during the second world war, and it was brought to market in 1964 as a cessation aid under the brand name Tabex, now produced by Sopharma, a Bulgarian drug company. Currently, the recommended course of treatment starts at one tablet every two hours (six in total per day) for one to three days, tapered gradually, with a scheduled quit date at day 5, and ending with one to two tablets daily by days 21-25. Optimal doses and duration of treatment, however, are as yet undetermined because no human pharmacokinetic data have been published.

The …