tbuckley/cabot-search huggingface dataset:
Abstract 5398: In vivo development of pan-Pim kinase small molecule inhibitors
Authors: Bethany Mattson, Christine. E. Sastri, Nadia Guerrero, Dean Hickman, Jie Chen, Tian Wu, Hui-Ling Wang, Andrew Taskar, Brian Lanman, Anthony B. Reed, Jude Canon, J. Russell Lipford, Karen Rex
Journal: Cancer Research (2015)

Abstract Pim-1,-2, and -3 are constitutively active serine-threonine kinases which are partially redundant and regulate multiple pathways important for tumor growth and survival. One or more of the human Pims are over-expressed in multiple hematological tumor types (e.g. multiple myeloma (MM), NHL and AML) and in some solid tumors (e.g. prostate and SCLC). Pim over-expression correlates with malignancy and poor prognosis in several indications. Our goal was to generate a pan Pim kinase inhibitor with acceptable physical chemical properties and in vivo anti-tumor efficacy. Here we present data on two ATP-competitive, orally bioavailable pan Pim inhibitors, Compound I and Compound II. These inhibitors have potent enzymatic and cellular activity, acceptable pharmacokinetic properties (PK) and robust in vivo efficacy. In a kinase enzyme assay Compound I inhibits Pim-1 and Pim-2 activity with 0.4 nM and 0.7 nM IC50s, respectively, while Compound II is even more potent with Pim-1 and Pim-2 IC50s of 0.1 nM/0.1 nM. In a cellular assay which measures inhibition of the Pim downstream substrate phospho-BAD (p-BAD), compounds I and II demonstrate IC50s of 56 and 16 nM, respectively. In an in vivo pharmacodynamic assay (PD) to demonstrate on-target Pim activity, compounds I and II significantly inhibited p-BAD in KMS-12-BM multiple myeloma tumors for 16 hours post dose. Treatment of KMS-12-BM tumor xenografts with Compound I demonstrated robust in vivo anti-tumor efficacy resulting in 23% tumor regression at 50 mg/kg BID and tumor stasis at 100 mg/kg QD. Compound II demonstrated improved PK properties leading to greater anti-tumor efficacy of 33% tumor regression at 100 mg/kg QD and tumor stasis at 50 mg/kg QD. Compound II showed efficacy in an orthotopic model of multiple myeloma and in models of AML and DLBCL. Combination treatment of Compound II and the standard of care Dexamethasone in the multiple myeloma RPMI-8226 xenograft model demonstrated enhanced tumor growth inhibition compared to either single agent activity. In summary, Compound I and II are potent and selective inhibitors of Pim kinases with excellent in vivo properties. Pim kinase inhibitors, either as monotherapy or in combination with dexamethasone, may be effective clinical strategies for certain cancer patients. Citation Format: Bethany Mattson, Christine. E. Sastri, Nadia Guerrero, Dean Hickman, Jie Chen, Tian Wu, Hui-Ling Wang, Andrew Taskar, Brian Lanman, Anthony B. Reed, Jude Canon, J. Russell Lipford, Karen Rex. In vivo development of pan-Pim kinase small molecule inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5398. doi:10.1158/1538-7445.AM2015-5398
Cystatin M is a putative tumor suppressor gene in melanoma
Authors: Jon Briggs, Gunhild Maelandsmo, Oystein Fodstad, Adam Riker
Journal: Cancer Research (2007)

487   The purpose of this study was to investigate the tumor suppressive properties of the cysteine protease inhibitor cystatin E/M (cystatin M) in melanoma. A variety of proteases have been shown to be important in tumor progression, and the loss of endogenous protease inhibitors may result in increased protease  expression in cancer. Recent studies have indicated that loss of cystatin M expression leads to increased growth and metastatic potential in breast cancer. However, the role of cystatin M in melanoma growth and metastasis is not clearly defined. To identify specific genes that may be important in melanoma progression, microarray studies were performed comparing gene expression profiles between cultured human melanocytes (NHEM), normal human skin, early primary and metastatic melanoma samples. These studies revealed that cystatin M gene expression was present in normal human skin but markedly down-regulated during progression from primary to metastatic melanoma. Genomic analysis showed only minimal cystatin M gene expression in NHEM. Analysis of daughter cell lines derived from the freshly procured samples revealed that cystatin M protein expression was absent in the majority of cell lines established from metastases, whereas low levels of protein expression were detected in several of the cell lines derived from primary melanomas. Transfection of the daughter cell lines with cystatin M resulted in marked growth inhibition. A potential mechanism for this growth inhibition appears to involve a substantial decrease in ERK phosphorylation. More detailed mechanistic studies are currently underway, and  in vivo  studies examining the role of cystatin M on melanoma growth and metastasis are being performed. In summary, we have identified cystatin M as a putative tumor suppressor gene in melanoma, with the gene expression pattern revealing a clear inverse correlation between cystatin M expression and increasing metastatic capability from primary melanoma of increasing tumor thickness to metastatic melanoma. In addition, we show that cystatin M is capable of suppressing melanoma cell growth  in vitro  via the inhibition of the RAF/MEK/ERK pathway, and overall these studies suggest that cystatin M has a tumor suppressive function in melanoma.
Dedication to Alan N. Houghton, MD
Authors: Daniel G. Coit
Journal: Journal of the National Comprehensive Cancer Network (2009)

In 1997, Alan Houghton accepted the position as chairman of the newly assembled NCCN Melanoma Committee.It was from this group of knowledgeable, often opinionated, and occasionally contentious experts in the clinical management of melanoma that the original guidelines were forged.Beginning with the process of birthing the guidelines and continuing throughout their scheduled reviewing and updating over the past 12 years, Alan's quiet and consistent leadership has encouraged each member's opinion to be heard, emphasized the primacy of data over personal bias, and acknowledged the legitimate controversy of differing approaches to various aspects of melanoma patient care (both in the presence and in the absence of data).Whenever the discussion would digress into questions of managing unusual clinical scenarios, he would keep the group focused on the task at hand, sensibly invoking his "5% Rule," that guidelines could not possibly substitute for sound clinical judgment in dealing with uncommon events.In many ways, the NCCN Melanoma Guidelines embody Alan's lifelong commitment to better understanding the complex biology of melanoma, and to applying that knowledge to improve the care of patients afflicted with this disease.On behalf of the NCCN Melanoma Committee, with enormous gratitude and unlimited respect, we would like to dedicate this issue of
Safety and efficacy of rapid (1,000 mg in 1 hr) intravenous iron dextran for treatment of maternal iron deficient anemia of pregnancy
Authors: Lee Wong, Samuel Smith, Marisa Gilstrop, Richard Derman, Sarah Auerbach, Nicola London, Steven Lenowitz, Huzefa Bahrain, Jessica McClintock, Michael Auerbach
Journal: American Journal of Hematology (2016)

Maternal iron deficiency anemia (IDA) is associated with risk of adverse perinatal outcomes. Oral iron is recommended to reverse anemia, but has gastrointestinal toxicity and frequent non‐adherence. Intravenous (IV) iron is reserved for intolerance of, or unresponsiveness to, oral therapy, malabsorption, and severe anemia (1% with hemoglobin [Hgb] levels &lt;7 g/dL). With rare (&lt;100 per one million) adverse events (AEs) ability to infuse a sufficient dose of low molecular weight iron dextran (LMWID) over 60 min, LMWID is an attractive option. This study demonstrated safety and efficacy of rapid IV infusion of 1,000 mg LMWID to gravidas with moderate to severe IDA. An observational treatment study of 1,000 mg LMWID administered over 1 hr for IDA in 189 consecutive, unselected second and third trimester gravidas after oral iron failure was conducted. All received a test dose of 25 mg LMWID and were monitored for AEs during the 60‐min infusion. No premedication was administered unless more than one drug allergy or asthma was present in which case IV methylprednisolone was administered. All were followed through pregnancy and delivery. Monitored parameters included Hgb, mean corpuscular volume, serum ferritin, and percent transferrin saturation. About 189 subjects received 1,000 mg LMWID. No serious AEs occurred. About 2% experienced transient infusion reactions. Hgb improved by 1–1.9 g/dL in 82% and ≥2 g/dL in 24%. Second trimester treatment was not associated with greater Hgb improvement than third trimester treatment. Anemia resolved in 95%. Administration of a single large dose of IV LMWID was effective, safe, and convenient. Am. J. Hematol. 91:590–593, 2016. © 2016 Wiley Periodicals, Inc.
Parishin C's prevention of Aβ1–42-induced inhibition of long-term potentiation is related to NMDA receptors
Authors: Zhihui Liu, Weiping Wang, Nan Feng, Ling Wang, Jiangong Shi, Xiaoliang Wang
Journal: Acta Pharmaceutica Sinica B (2016)

The rhizome of Gastrodia elata (GE), a herb medicine, has been used for treatment of neuronal disorders in Eastern Asia for hundreds of years. Parishin C is a major ingredient of GE. In this study, the i.c.v. injection of soluble Aβ1–42 oligomers model of LTP injury was used. We investigated the effects of parishin C on the improvement of LTP in soluble Aβ1–42 oligomer–injected rats and the underlying electrophysiological mechanisms. Parishin C (i.p. or i.c.v.) significantly ameliorated LTP impairment induced by i.c.v. injection of soluble Aβ1–42 oligomers. In cultured hippocampal neurons, soluble Aβ1–42 oligomers significantly inhibited NMDAR currents while not affecting AMPAR currents and voltage-dependent currents. Pretreatment with parishin C protected NMDA receptor currents from the damage induced by Aβ. In summary, parishin C improved LTP deficits induced by soluble Aβ1–42 oligomers. The protection by parishin C against Aβ-induced LTP damage might be related to NMDA receptors.
Reactivity profiles of leukemic myeloblasts with monoclonal antibodies directed to sialosyl-Le(x) and other lacto-series type 2 chain antigens:absence of reactivity with normal hematopoietic progenitor cells
Authors: K Muroi, T Suda, H Nojiri, H Ema, Y Amemiya, Y Miura, H Nakauchi, A Singhal, S Hakomori
Journal: Blood (1992)
Angiotensin II type 1 receptor antagonists in animal models of vascular, cardiac, metabolic and renal disease
Authors: Martin C. Michel, Hans R. Brunner, Carolyn Foster, Yong Huo
Journal: Pharmacology & Therapeutics (2016)

We have reviewed the effects of angiotensin II type 1 receptor antagonists (ARBs) in various animal models of hypertension, atherosclerosis, cardiac function, hypertrophy and fibrosis, glucose and lipid metabolism, and renal function and morphology. Those of azilsartan and telmisartan have been included comprehensively whereas those of other ARBs have been included systematically but without intention of completeness. ARBs as a class lower blood pressure in established hypertension and prevent hypertension development in all applicable animal models except those with a markedly suppressed renin–angiotensin system; blood pressure lowering even persists for a considerable time after discontinuation of treatment. This translates into a reduced mortality, particularly in models exhibiting marked hypertension. The retrieved data on vascular, cardiac and renal function and morphology as well as on glucose and lipid metabolism are discussed to address three main questions: 1. Can ARB effects on blood vessels, heart, kidney and metabolic function be explained by blood pressure lowering alone or are they additionally directly related to blockade of the renin–angiotensin system? 2. Are they shared by other inhibitors of the renin–angiotensin system, e.g. angiotensin converting enzyme inhibitors? 3. Are some effects specific for one or more compounds within the ARB class? Taken together these data profile ARBs as a drug class with unique properties that have beneficial effects far beyond those on blood pressure reduction and, in some cases distinct from those of angiotensin converting enzyme inhibitors. The clinical relevance of angiotensin receptor-independent effects of some ARBs remains to be determined.
Long-Term Post-Discharge Risks in Older Survivors of Myocardial Infarction With and Without Out-of-Hospital Cardiac Arrest
Authors: Christopher B. Fordyce, Tracy Y. Wang, Anita Y. Chen, Laine Thomas, Christopher B. Granger, Benjamin M. Scirica, Timothy D. Henry, Graham C. Wong, Krishnan Ramanathan, Carolina M. Hansen, Kristian Kragholm, Eric D. Peterson, Monique L. Anderson
Journal: Journal of the American College of Cardiology (2016)
TCTAP A-151 Complete Versus Incomplete Revascularization in Patients with Multivessel Coronary Artery Disease Treated with Drug-Eluting Stents
Authors: Mineok Chang, Jung-Min Ahn, Duk-Woo Park, Pil Hyung Lee, Jae-Hyung Roh, Sung Han Yoon, Soo-Jin Kang, Seung-Whan Lee, Young-Hak Kim, Cheol Whan Lee, Seong-Wook Park, Seung-Jung Park, Se Hun Kang, Cheol Hyun Lee, Min Soo Cho, Jae Seok Bae, Yu Na Kim, Do-Yoon Kang
Journal: Journal of the American College of Cardiology (2016)
TCTAP A-022 In Hospital Clinical Outcome &amp; Coronary Angiographic Profile of Patient with Non-STEMI &amp; CKD Admitted in a Tertiary Care Centre, Dhaka, Bangladesh
Authors: C.M. Shaheen Kabir, M. Maksumul Haq, Saidur Rahman Khan, Fazila Tun-Nesa Malik, M. Liaquat Ali, Mashhud Zia Chowdhury, M.A. Rashid, Rezaul Karim, Mah-Noor Jahan
Journal: Journal of the American College of Cardiology (2016)
Abstract P2-03-04: Down-regulation of Bcl2-related ovarian killer (BOK) by miR-296-5p protects breast cancer cells from paclitaxel-induced apoptosis
Authors: BC Onyeagucha, S Rajamanickam, P Subbarayalu, B Bansal, H Bansal, Y-F Chang, S Timilsina, N Abdelfaltah, VK Eedunuri, MK Rao
Journal: Cancer Research (2016)

Abstract Accumulating evidence shows that miRNAs play a role in drug resistance. Despite these observations, little is known about the identities of the miRNAs involved in drug resistance and their downstream targets. In the present study, we identified miR-296-5p for which a tumor suppressive role has been previously described, as a miRNA that is involved in paclitaxel drug resistance in triple negative breast cancer (TNBC) cells. Enforced expression of miR-296-5p suppressed cell growth, migration, and invasion in MDA-MB-231 breast cancer cells. Using a microarray approach, we identified BCL2-related Ovarian Killer (BOK), a pro-apoptotic gene as a target of miR-296-5p. BOK levels were validated BOK levels in miR-296-5p transfected MDA-MB-231 and MDA-MB-468 cells using real-time PCR and Western blot. Our results demonstrated that over-expression of miR-296-5p down-regulated BOK expression in TNBC cells. Transfection of miR-296-5p significantly suppressed luciferase reporters containing wild-type BOK-3'-UTR constructs. In contrast, mutant BOK-3'-UTR constructs were unaffected by ectopic miR-296-5p. Furthermore, BOK expression was induced in the presence of paclitaxel, but ectopic miR-296-5p significantly suppressed BOK induction by paclitaxel treatment compared to the control cells. These data provide new insights on the role of miRNAs in drug resistance and suggests that therapeutic strategies against miR-296-5p may be warranted. Citation Format: Onyeagucha BC, Rajamanickam S, Subbarayalu P, Bansal B, Bansal H, Chang Y-F, Timilsina S, Abdelfaltah N, Eedunuri VK, Rao MK. Down-regulation of Bcl2-related ovarian killer (BOK) by miR-296-5p protects breast cancer cells from paclitaxel-induced apoptosis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-03-04.
PTU-045 Smokers with inflammatory bowel disease have low nicotine dependence
Authors: M Wahed, J R Goodhand, O West, A McDermott, P Hajek, D S Rampton
Journal: Gut (2010)

<h3>Introduction</h3> Smoking is a risk factor for developing Crohn9s disease (CD) and worsens its outcome. Conversely, the onset of ulcerative colitis (UC) may be triggered by smoking cessation and smoking may be beneficial. Successful smoking cessation is inversely related to nicotine dependence. We aimed to assess smoking dependence in inflammatory bowel disease (IBD) patients compared to healthy and disease-matched controls and individuals’ smoking knowledge. <h3>Methods</h3> 255 IBD patients (182CD:73UC) completed a questionnaire on smoking habits and its effect on IBD. Smokers were assessed for dependence using the Fagerstrom Test for Nicotine Dependence (FTND) score (1) (0–2 very low, 3–4 low,5 medium, 6–7 high, 8–10 very high dependence) compared to age, sex and ethnicity-matched healthy (5 subjects for each case) and asthma controls attending a smoking cessation clinic. The median (range) age was 38 (18–90) years and disease duration 9 (1–54) years for the IBD patients. Differences were sought using χ<sup>2</sup> test in categorical and Wilcoxon signed rank or Mann–Whitney U test in continuous data. <h3>Results</h3> 35/182 (19%) CD and 9/73 (12%) UC were current smokers. In CD, the median (range) FTND score was 3 (0–8) compared to 7 (2–10) in healthy (p&lt;0.001) and 6 (2–9) in asthma controls (p&lt;0.001). Only six of the 35 (17%) CD patients were highly dependent (FTND score ≥ 6). Smoking dependence was unrelated to ethnicity. Similarly, in UC the FTND score was 1 (0–4), lower than healthy 6 (2–10) and asthma controls 7 (4–10) (p&lt;0.004 for both groups). There was no difference in dependence between CD and UC patients. 88% CD smokers were interested in stopping smoking and 33% would consider attending a smoking cessation clinic. Patients with CD were better informed about the effects of smoking on their own disease compared to UC patients: 66/112 (59%) of CD patients knew that smoking worsens CD, whereas only 6/73 (8%) UC patients knew of the beneficial effects of smoking on their disease (p=0.0001). Knowledge was unrelated to smoking status. <h3>Conclusion</h3> A smaller proportion of our CD patients are smokers than has been reported in previous series (26–61%). Most patients with CD, regardless of their smoking status, recognise the detrimental effects of smoking on their disease. Nicotine dependence in IBD patients is lower than in smokers’ clinic clients and comparable to the general population. The level of interest in smoking cessation is high. Their low nicotine dependence suggests that most IBD patients could be weaned off smoking successfully in the IBD clinic and may not need referral to a smoking cessation clinic.
APX3330 inhibition of the redox function of ape-1/ref-1 (Ref-1) in promyelocytic leukemia cells enhances retinoic acid (ATRA) induced myeloid differentiation and limits cell proliferation as an approach to the prevention of the retinoic acid syndrome (RAS)
Authors: K. A. Robertson, E. S. Colvin, M. R. Kelley, M. L. Fishel
Journal: Journal of Clinical Oncology (2009)

e14613 Background: ATRA + chemotherapy has improved the treatment of promyelocytic leukemia(APL). However, 25% of ATRA treated APL patients experience toxicities that comprise the RAS (life-threatening respiratory distress, edema, renal failure, hypotension, coagulopathy and rising blast count). One approach to prevent RAS is to limit blast proliferation and enhance myeloid differentiation. Ref-1 is a DNA repair protein that functions in redox regulation of cellular proteins, such as Fos, Jun, p53, and NFkB. HL60 myeloid leukemia cells are promyeloblasts that respond to ATRA with granulocytic differentiation/growth arrest. Prior studies suggest Ref-1 redox control is integral to ATRA-induced differentiation. To define the role of the redox function of Ref-1, we used the Ref-1 specific drug, APX3330, to block Ref-1 redox function and examined the response of HL60 cells to ATRA. Methods: Cell growth assessed using trypan blue. Differentiation was evaluated by morphology and expression of CD11b by flow cytometry. Apoptosis was assayed by annexin-PI staining on flow cytometry and cell cycle analysis assayed with propidium iodide flow cytometry. To assess activation of the MAPK pathway, BLR-1 expression was determined by real time PCR. Results: 1) APX3330 blockade of Ref-1 redox function resulted in limited cell growth yet a profound increase in differentiation and a moderate increase in apoptosis. 2) dose dependent studies with ATRA showed a similar degree of differentiation in cells treated with 10 μM ATRA to cells treated with APX3330 + 0.01 μM ATRA; allowing HL60 cells + APX3330 to give a similar response to a 1000 fold lower dose of ATRA. APX3330 alone did not induce differentiation and induced only minimal apoptosis but in combination with ATRA, increased the number of cells in G1/G0 phase significantly. 3) APX3330 + ATRA increased BLR-1 expression significantly by real time PCR suggesting enhanced activation of the MAPK pathway. Conclusions: APX3330 + ATRA limits HL60 growth and dramatically enhances terminal granulocytic differentiation. These finding may provide a therapeutic approach for prevention of the RAS. No significant financial relationships to disclose.
Book: Women and Schizophernia · Women and Mental Health
Authors: Helen Pattison
Journal: BMJ (2001)

Women and Schizophrenia. Eds David J Castle, John McGrath, Jayashri Kulkarni. Cambridge University Press, £18.95, pp 164. ISBN 0 521 78617 7. Rating: ★★ 

Women and Mental Health by Dora Kohen. Routledge, £16.99, pp 250. ISBN 0 415 18885 7. Rating: ★★★


Research in medicine is often, in practice, research in medicine for men. Doing research on people who have regularly fluctuating hormone levels is regarded as too tricky unless, of course, those hormones are themselves seen as the cause of the problem. And those hormones are often regarded as the most likely culprits when sex differences are observed in the incidence and prevalence of disease, or response to treatment. These issues are writ large in both of these books. 






Women and Schizophrenia is at its best when addressing the impact of schizophrenia on women's lives and the ways in which treatment regimes can help to alleviate problems which are often secondary to the illness itself. Other areas are covered less satisfactorily. For example, the chapter on brain sex differences devotes a large section to the neurodevelopmental effects of testosterone on male brains. The limitation of the authors' explanation of sex differences in behavioural symptoms of schizophrenia to differences in neurodevelopment ignores work on cultural effects showing that judgments about acceptable or abnormal behaviour are often gender rather than sex based.

On the whole, this is a clearly written and well presented book, but, in an area fraught with methodological problems, the authors could have been more critical of the findings they report and cast their net more widely.

Turning to the chapter on schizophrenia in Women and Mental Health, we find much of the same material as above, but here it is dealt with in a more parsimonious and critical fashion. The other chapters on particular conditions—depression, perinatal disorders, eating disorders, and substance misuse—are similarly impressive.

What is most unsatisfactory is the separation of these chapters from those on physiological, sociological, and psychological factors in women's mental health. This can lead to unnecessary repetition but more often leads to a lack of integration of material crucial to the understanding of the aetiology and epidemiology of psychiatric disorders.

These books show that mental health researchers and clinicians are developing more sophisticated explanations of the ways in which women's physiology interacts with the ways women live and the roles we play to produce particular patterns of mental health and mental illness. Clearly, however, there is still a great deal of research to be done.