tbuckley/cabot-search huggingface dataset:
Abstract 1634: A novel small molecule inhibitor of IRE1alpha reverses endocrine resistance in breast cancer cells
Authors: Ayesha N. Shajahan-Haq, Jacqueline Smith, Siva Dakshanamurthy, Difei Wang, Ahreej E. Eltayeb, Milton L. Brown, Robert Clarke
Journal: Cancer Research (2014)

Abstract Over two-thirds of all breast cancer patients are estrogen receptor alpha positive (ER+). However, almost 50% of all ER+ breast tumors do not respond or respond and later fail on endocrine therapy. Resistance to endocrine therapy remains a significant clinical problem and advanced ER+ breast cancer is largely an incurable disease. The mechanisms of resistance to endocrine therapy remain unclear. We have reported that the unfolded protein response (UPR), a stress-induced cellular adaptive mechanism, acts as a switch controlling the balance between cell death and cell survival in response to these therapies. UPR is activated by three molecular sensors: IRE1alpha, ATF6, PERK. Several components of the UPR, including IRE1alpha, are up-regulated in endocrine resistant cells. We now report a novel small molecule inhibitor of IRE1alpha: N-(4-Phenoxy-phenyl)-2-(5-pyridin-3-yl-2H-[1,2,4]triazol-3-ylsulfanyl)-acetamide (NPPTA). We show that NPPTA interacts with IRE1alpha in vitro and can decrease IRE1alpha protein levels. NPPTA treatment alone inhibits cell proliferation in antiestrogen resistant ER+ breast cancer cells more effectively than in sensitive cells, and in a dose- and time-dependent manner. Normal breast epithelial cells are unaffected by NPPTA. In addition, NPPTA and TAM synergistically inhibit cell proliferation in TAM resistant breast cancer cells. NPPTA's activities are associated with induced G1 cell cycle arrest, increased apoptosis/necrosis, and inhibition of anti-apoptotic signaling. Targeting IRE1alpha may be a new and effective strategy to reverse endocrine resistance in breast cancer. Citation Format: Ayesha N. Shajahan-Haq, Jacqueline Smith, Siva Dakshanamurthy, Difei Wang, Ahreej E. Eltayeb, Milton L. Brown, Robert Clarke. A novel small molecule inhibitor of IRE1alpha reverses endocrine resistance in breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1634. doi:10.1158/1538-7445.AM2014-1634
Abstract 205: Variability of Chest Compression Duty Cycle in the Treatment of Out-of-Hospital Cardiac Arrest
Authors: Jessica A Cutler, David D Salcido, James J Menegazzi
Journal: Circulation (2014)

Background: The duty cycle (DC) of cardiopulmonary resuscitation (CPR), which, from the start of one compression to the start of the next compression, describes the proportion of time spent compressing the chest downward, may be useful for characterizing CPR quality. Fifty percent is considered an optimal CPR DC, but little is known about real world DC characteristics. Objective: To describe DC characteristics of CPR delivered during the treatment of out-of-hospital cardiac arrest (OHCA). Methods: Defibrillator download files for cases of OHCA treated by emergency medical services (EMS) between 2006 and 2008 were obtained from the Pittsburgh regional clinical center of the Resuscitation Outcomes Consortium (ROC), a multi-center clinical research network. Compression depth data were imported into custom software, screened for artifacts, and then parsed and analyzed to establish start, end, and maximum depth for each compression. DC was calculated as the proportion of a compression prior to maximum depth. Descriptive statistics were reported for compression depth in centimeters, rate in compressions per minute (CPM) and DC, averaged over each minute of CPR for up to 30 minutes. Generalized estimating equations (GEE) were used to model the relationship between DC and rate, depth and time. Results: The 328 cases included in this study had a mean (SD) age of 64.9 (16.7) years and were predominantly male (61.9%, SE: 2.7). A total of 393,013 analyzable compressions were detected. Figure 1 shows the average CPR DC, rate and depth over the first 30 minutes. Average DC for this period ranged from 44.0% to 46.7%. Mean (SD) DC for the entire 30 minute period was 45.6% (5.2). In a GEE model, DC was inversely related to rate (coeff: -0.0004, p&lt;0.001) and time (coeff: -0.0006, p&lt;0.001), but directly related to depth (coeff: 0.0038, p&lt;0.001). Conclusions: DC in EMS-treated OHCA cases was less than the 50% standard, decreased over time, and correlated with both compression rate and depth.
Wiskott-Aldrich Syndrome/X-Linked Thrombocytopenia: WASP Gene Mutations, Protein Expression, and Phenotype
Authors: Qili Zhu, Chiaki Watanabe, Ting Liu, Diane Hollenbaugh, R. Michael Blaese, Steven B. Kanner, Alejandro Aruffo, Hans D. Ochs
Journal: Blood (1997)
Abstract P330: Cardiovascular Adipose Depots Of The Heart And Aorta Are Associated With CVD Risk Factors And Vascular Calcification In Women With SLE
Authors: Kelly J Shields, Joseph M Ahearn, Susan Manzi
Journal: Circulation (2014)

Introduction: Women with systemic lupus erythematosus (SLE) are at greater risk of developing cardiovascular disease (CVD), which is not explained by traditional CVD and SLE-related risk factors. Mounting evidence implicates small visceral adipose depots surrounding the heart and vasculature in the pathogenesis of CVD. Previously, we found that women with SLE had a greater volume of aortic perivascular adipose tissue (aPVAT) compared to healthy controls (HC). Here we quantify epicardial (EPI), paracardial (PARA), and total heart (TOT = EPI+PARA) adipose and evaluate their associations with aPVAT, CVD risk factors and coronary artery (CAC) and aortic (AC) calcification. Design: Data included clinically CVD-free SLE women never (SLEc-) or ever (SLEc+) on corticosteroids, and healthy controls (HC) (HEARTS cohort). Electron beam CT scans were used to quantify adipose depots and AC/CAC. Logistic and linear regressions were used and final models were adjusted for waist-to-hip ratio. Results: In this study, age- and race-matched women participated: 15 SLEc-, 15 SLEc+, and 15 HC. More SLE women had hypertension (p=0.04), elevated circulating eSelectin (p=0.04), albumin (p=0.01), and homocysteine (p=0.02) compared to HC. SLEc+ women had decreased circulating C3 (p=0.04) and C4 (p&lt;0.01) compared to SLEc- women. TOT tended to be greater in SLE (mean(std): 108(92)cm3, p=0.07) vs. HC (85.2(30) cm3) and in SLEc+ (122(45) cm3,p=0.06) vs. vs SLEc- (93.5(32) cm3). There were no differences in EPI (p=0.2) or aPVAT (p=0.3), but PARA was greater in SLEc+ (54.2(27) cm3) vs. SLEc-(36.9(19) cm3) (p=0.05). TOT was correlated with aPVAT in SLE (rho,p: 0.47, 0.01) and HC (0.69, &lt;0.01) with PARA volume (SLE(0.43, 0.02) and HC (0.57, 0.03)) driving this association. In HC, EPI and PARA were correlated with insulin (p&lt;0.03) and HOMA-IR (p&lt;0.04) while PARA was correlated with CRP (p=0.04). Glucose levels were correlated with EPI in SLEc+ (0.53, 0.04) and with PARA in SLEc- (-0.55, 0.03). AC was detected in 21/28 SLE women and 11/15 HC while CAC was detected in 13/28 SLE and 4/15 HC. Only aPVAT was associated with increasing AC (OR(95%CI),p): 1.09 (1.0-1.2), 0.04) and CAC (1.11 (1.0-1.2), 0.03) in SLEc+. In adjusted models, only aPVAT(log) remained associated with greater extent of AC in SLE(β(SE),p: 2.90(1.3), 0.04), which was driven by SLEc+ (5.13(1.8), 0.02) women. Conclusion: Adipose depots surrounding the heart and vasculature are greater in clinically CVD-free women with SLE and specifically SLEc+, with significant associations among CVD risk factors and calcification dependent on their location. Corticosteroid treatment may suppress circulating inflammatory markers, but is associated with greater adipose volumes surrounding the heart and increased calcification. Just as AC generally precedes CAC development, aPVAT may be a precursor to extensive PARA and EPI development, with PARA more strongly associated.
Phosphorylation of Chk2 and H2AX during gemcitabine-induced S-phase arrest
Authors: Brett Ewald, Jingxuan Pan, Deepa Sampath, William Plunkett
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

2267 

Gemcitabine is a nucleoside analog that is incorporated into replicating DNA, resulting in partial chain termination and stalling of replication forks. Human AML leukemia cells (ML-1) arrest in S phase when exposed to 7.5-10 nM gemcitabine for 24 h. The goal of this investigation was to investigate the molecular pharmacology of the gemcitabine-induced S-phase checkpoint. Under S-phase arrest conditions, the DNA damage-responsive kinase, Chk1, was phosphorylated on Ser-317 and Ser-345, indicating its activation by an upstream sensor(s). Consistent with S-phase checkpoint activation, phosphorylation of cyclin-dependent kinase 2 (Cdk2) on Y-15 increased in comparison with untreated controls, indicating its inhibition. Chk2 is a second kinase that is responsive to DNA damage, but its role in S-phase arrest has not been established. Phosphorylation of Thr-68 of Chk2 demonstrated that it also became activated in response to gemcitabine treatment. H2AX, a histone that rapidly undergoes phosphorylation and forms microscopic nuclear foci after recruitment to sites of DNA damage, also became phosphorylated on Ser-139 within 2 h after gemcitabine treatment, as determined by confocal microscopy and flow cytometry. Thus, these responses of Chk2 and H2AX to gemcitabine suggest the presence of DNA damage, that is qualitatively different from that which activates the canonical Chk1-Cdc25A-Cdk2/Cyclin A checkpoint pathway. Exposure of S-phase arrested cells to the Chk1 inhibitor, 7-hydroxystaurosporine (UCN-01, 100 nM), resulted in an abrogation of the S phase checkpoint and an increase in cell death within 3 h that exceeded 35% of the population by 9 h. In contrast, UCN-01 alone (10-200 nM) had little effect on the cell cycle status or viability of exponentially growing ML-1 cells. Consistent with such abrogation, a significant dephosphorylation of Cdk2 on Tyr-15 was observed, while total Cdk2 levels remained stable. Phosphorylation of Chk1 on Ser-317 and Ser-345 increased within 3 h of UCN-01 addition as did phosphorylation of Chk2 kinase and H2AX, in comparison to levels in S-phase arrested cells. These events, perhaps in response to a second set of DNA damage sensors that may govern apoptosis, signal additional DNA damage upon UCN-01 addition.
Abstract 4413: Mnk activity in diffuse large b-cell lymphoma: targeting translation
Authors: Ari Landon, Parameswary A. Muniandy, Ronald B. Gartenhaus
Journal: Cancer Research (2014)

Abstract Augmentation of protein translation has been observed in a number of human malignancies. We have previously demonstrated that cap-dependent protein translation is dysregulated in diffuse large B-cell lymphoma (DLBCL). This cancer-associated phenomenon may result in the deregulation of many proto-oncogenes and tumor suppressors leading to multiple cellular abnormalities. A major rate-limiting step in cap-dependent translation is the binding of eIF4E to the 7-methyl guanosine cap in the 5′ untranslated region of mRNA thus, bridging the eIF4F pre-initiation complex with the ribosome and initiating translation. eIF4E has been widely implicated as a proto-oncogene contributing to cancer development in numerous published reports. In addition to the mTOR signaling network, there is a potential for eIF4E to be modulated by the mitogen-activated protein kinases via map kinase interacting kinases (MNK). MNK proteins (MNK1 or MNK2) exert their effect on eIF4E through phosphorylation of eIF4E at serine 209. This phosphorylation is believed to promote B-cell lymphomagenesis. However, the physiologically relevant regulatory mechanisms and potential for targeting eIF4E phosphorylation in human B-cell lymphoma is largely unexplored. This study aims to elucidate the mechanistic and therapeutic effects of MNK regulation of eIF4E phosphorylation in DLBCL. Counter-intuitively, we have found differential expression of MNK2 over MNK1 in activated B-cell (ABC) lymphoma versus germinal center B-cell (GCB) lymphoma subtypes even though both are known to converge to phosphorylate eIF4E. Interestingly, ERK does not play a significant role in activating MNK1/2 or affect the downstream phosphorylation of eIF4E in DLBCL, however, p38 plays an important role in eFI4E phosphorylation via MNK1. We show that phosphorylation of eIF4E by MNK is critical for malignant cell survival in both ABC and GCB DLBCL. The inhibition of p38 resulted in a significant and selective killing of DLBCL via inactivation of MNK1 and down-regulation of MCL1. Therefore, p38 inhibition may be a useful targeted approach in DLBCL through its suppression of MNK mediated eIF4E phosphorylation. Citation Format: Ari Landon, Parameswary A. Muniandy, Ronald B. Gartenhaus. Mnk activity in diffuse large b-cell lymphoma: targeting translation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4413. doi:10.1158/1538-7445.AM2014-4413
Physiotherapy led weaning plans reduce the number of days patients require non-invasive ventilation (NIV)
Authors: Stephanie Harlow, Amber Lane, Paul Murray
Journal: European Respiratory Journal (2012)

Background   Respiratory physiotherapists at ASPH assess, monitor and wean patients requiring NIV. In May 2009, as a result of previous NIV audit data, a physiotherapy led weaning proforma was implemented to improve successful weaning rates.   Aims and objectives   The aim of the investigation was to establish if physiotherapy led weaning plans reduced the number of days patients spent on NIV.   Methods   Data were collected prospectively from 255 consecutive patients requiring NIV over a two year period from May 2009 to April 2011 using a locally adapted version of the BTS NIV data collection tool. Number of days on NIV were collected from patients nursing notes. 84 patients had physiotherapy led weaning plans and were included in the analysis (t-test).   Results   33% (n=84) of patients had a physiotherapy led weaning plan. The impact of physiotherapy led weaning plans is summarised.  8% (n=21) patients required referral for domiciliary NIV and therefore could not be weaned and were excluded from the analysis.   Conclusion   Physiotherapy led weaning plans reduce the length of time patients remain on NIV. A possible explanation could be faster optimisation in the first 24 hours facilitating a shortened weaning time. Further investigation is required to establish if earlier physiotherapy input can impact on NIV outcome.   Thanks to Tina Thomas for data entry.
Abstract 12999: Senescence Marker Protein 30 Protect the Cardiac Injury From After Ischemia Reperfusion
Authors: Shinpei Kadowaki, Tetsuro Shishido, Taro Narumi, Yuki Honda, Satoshi Nishiyama, Hiroki Takahashi, Takanori Arimoto, Takuya Miyamoto, Tetsu Watanabe, Yasuchika Takeishi, Isao Kubota
Journal: Circulation (2014)

Background: Successful myocardial reperfusion is effective therapy for improving the clinical outcome after acute myocardial infarction, nevertheless reperfusion injury can paradoxically induces cardiomyocyte dysfunction. Moreover, recovery of cardiac function is impaired with aging. Glycogen synthase kinase-3β (GSK-3β) and p70 ribosomal S6 kinase (p70S6K) are cardioprotective against I/R via mitochondrial dysfunction. Senescence marker protein-30 (SMP30), which regulates mitochondrial quality and decreases with aging, is an organ-protective protein; however the protective role of SMP30 against ischemia/reperfusion (I/R) has not been clearly determined yet. Methods and Result: Firstly, we confirmed that SMP30 expressions in the heart were progressively decreased with aging. In vitro study, we also found that reactive oxygen species decreased expression levels of SMP30 in neonatal cardiomyocyte. Depletion of SMP30 increased apoptotic cardiomyocyte death after hydrogen peroxide stimulation. To evaluate the cardioprotective role of SMP30, we induced 30 min ischemia and 24-hr reperfusion (I/R) in WT and SMP30 KO mice. Phosphorylation levels of p70S6K and GSK-3β in the heart were increased after IR in WT mice; however those phosphorylation were attenuated in SMP30 KO mice. SMP30 KO mice after I/R had significantly larger numbers of apoptotic cardiomyocyte than WT mice ( 10.5± 5.7% vs. 4.0± 1.7%, p &lt; 0.05), that correlated with a significant expansion in infarct size and a significant reduction of left ventricular fractional shortening (37.3± 4.3% vs 43.4± 5.1%, p &lt; 0.01). Conclusions: These results suggest that reduction of SMP30 levels with aging is associated with age-related dysfunction after ischemia-reperfusion through disability to phosphorylate p70S6K and GSK-3β. Thus, SMP30 might be a novel therapeutic target for the treatment of acute myocardial infarction in elderly patient.
Abstract 1149: Endothelial Dysfunction in AMP-activated Kinase {alpha}2 Knockout Mice: Role of NAD(P)H oxidase-derived Superoxide Anions
Authors: Shuangxi Wang, Jian Xu, Ping Song, Yong Wu, Minghui Zou
Journal: Circulation (2007)

Objective: AMP-activated kinase (AMPK) is a serine/threonine kinase and is activated by oxidant stress. Whether or not AMPK activation alters the balance of oxidants/antioxidant is unknown. The aim...
Psychiatric Dictionary With Encyclopedic Treatment of Modern Terms
Authors: Leland Earl Hinsie, Jacob Shatzky
Journal: JAMA (1941)

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The BMA's annual representative meeting
Authors: Linda Beecham
Journal: BMJ (1998)

# The BMA's annual representative meeting {#article-title-2}

At its first annual meeting since the publication of the NHS white papers the BMA has called for no restructuring of the NHS or major changes to go ahead without prior testing and evaluation. Dr Brian Keighley (Forth Valley) said that the government must not fall into the trap of previous administrations. Most doctors in the hall had seen two or three major changes based on the political flavour of the time and they should be properly evaluated.

The BMA's annual representative meeting was held in Cardiff from 6 to 9 July. It was chaired by Dr Jane Richards, a former GP in Exeter. She will be succeeded next year by her deputy, Professor Brian Hopkinson, a consultant surgeon in Nottingham, with Dr George Rae, a GP in north Tyneside as his deputy. Sir Alexander Macara's last address to the ARM as chairman of council was reported on 11 July (p 98). An interview with the new chairman of the BMA council, Dr Ian Bogle, is on p 166.

But Dr David Brownridge (local medical committee (LMC) conference) pointed to the agreement between the government and the General Medical Services Committee (GMSC) on primary care groups (PCGs). This was not received with universal acclaim and there was no mention of pilots. The negotiators should have made proper pilots a major negotiating skill. He was supported by Dr David Cairns (council) who said that first trusts and now PCGs had been imposed.

Both were roundly opposed by the GMSC chairman, Dr John Chisholm. “We are committed to evidence based policy making but where we see that something is wrong we want to get on and change it,” he said. He feared that the motion could be interpreted in the future to use pilots to delay necessary change.

A newly qualified …
Abstract 3606: Reversible Myocardial Injury, but not Microvascular Obstruction, is Major Pathophysiology of Takotsubo Cardiomyopathy Detected by Contrast-Enhanced Magnetic Resonance Imaging
Authors: Teruo Noguchi, Naoaki Yamada, Hiroshi Nonogi, Yoichi Goto, Rika Kawakami, Yasuyo Taniguchi, Taiki Higo
Journal: Circulation (2006)
Abstract #5496: siRNA target selection using machine learning techniques: Genes implicated in aggressive prostate cancer
Authors: Parker Matthew, Colin Campbell, Luke Carrivick, Colin Cooper
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Distinguishing between indolent and aggressive forms of prostate cancer remains a significant clinical problem, existing markers which define these cancers are inadequate. We urgently need to replace these with more reliable and robust alternative biomarkers to spare those with indolent cancers the morbidity of treatment and ensure those with clinically relevant cancers are treated. We have previously used an unsupervised learning technique called latent process decomposition to find additional structure in breast cancer expression microarray datasets. We have now applied this analytical approach to published prostate cancer expression microarray datasets leading to the discovery that prostate cancer may be divided into three prognostically distinct subgroups. Genes overexpressed in the aggressive subgroup were examined for biological function in prostate cancer cell lines using siRNA technology. Using this method we identified two genes, PSM\#946;5 (which encodes a \#946; subunit of the 20s and 26s proteasomes) and C7orf28A (which encodes a novel lysosomal protein) that were of particular interest. These genes, when silenced, significantly reduced growth and viability of prostate cancer cell lines PC3 and 22Rv1 at least in part by causing an increase in apoptosis. Quantitative RT-PCR studies confirmed that PSM\#946;5 is expressed at abnormally high levels in prostate cancer and antibodies raised against C7orf28A show reduced expression in normal prostate. This study illustrates the practical use of unsupervised learning methods in selecting genes of potential prognostic, therapeutic and functional interest.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5496.