tbuckley/cabot-search huggingface dataset:
Abstract 2120: Inhibition of multiple myeloma exosomes prevents bone loss and reduces tumor growth
Authors: Sylvia T. Faict, Kim De Veirman, Ken Maes, Elke De Bruyne, Roy Heusschen, Jo Caers, Karin Vanderkerken, Rik Schots, Eline Menu
Journal: Cancer Research (2018)

Abstract Multiple myeloma, one of the most common hematological malignancies, will often manifest osteolytic lesions during disease development, throughout the whole body. MM is still considered an incurable malignancy, with a supportive micro-environment in the bone marrow. Extracellular vesicles such as exosomes are known to play an important tumor-promoting role in this micro-environment, by inducing angiogenesis and immune suppression. The aim of our study was to examine the effects of MM exosomes on osteolysis in vitro and in vivo, and to determine whether inhibition of exosome secretion can lead to a delay in tumor growth and prevent bone loss. We used the 5TGM1 model which is a syngeneic murine MM model, presenting typical MM characteristics such as osteolysis, angiogenesis and a serum M-spike. We examined the effects of conditioned medium from these MM cells and MM-derived exosomes on cell viability and proliferation of the MC3T3 pre-osteoblast cell line and on their ability to produce alkaline phosphatase (ALP). We saw a decrease in viability and ALP activity when adding exosomes or conditioned medium of the 5TGM1 myeloma cells to the osteoblasts. Moreover, RT-PCR analysis showed a decrease of various osteogenic differentiation genes when osteoblasts were exposed to 5TGM1 exosomes, demonstrating a diminished capacity of osteoblastic differentiation. We next added the exosome secretion inhibitor GW4869 to the 5TGM1 cells, thereby reducing the number of exosomes in the conditioned medium. This was confirmed through western blot of the typical exosome markers. The negative effects of the 5TGM1 conditioned medium on osteoblasts could be overturned by reducing the exosome content therein. In vivo, we injected 5TGM1 exosomes intravenously in healthy mice for three weeks and examined the effects on osteolysis by microCT and TRAP staining. We saw an increase in osteolysis, comparable to the typical osteolytic lesions in tumor-bearing mice. Furthermore, when inhibiting the exosome secretion in vivo in 5TGM1 mice, we observed a significant reduction in tumor load. Through this study we can conclude that exosomes from multiple myeloma cells can induce osteolytic lesions by inhibiting osteoblast proliferation and differentiation. These effects can be reversed by inhibiting the secretion of exosomes. Citation Format: Sylvia T. Faict, Kim De Veirman, Ken Maes, Elke De Bruyne, Roy Heusschen, Jo Caers, Karin Vanderkerken, Rik Schots, Eline Menu. Inhibition of multiple myeloma exosomes prevents bone loss and reduces tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2120.
Cardioprotective Mechanism of Ischemic Preconditioning Is Impaired by Postinfarct Ventricular Remodeling Through Angiotensin II Type 1 Receptor Activation
Authors: TakayukiMiki, TetsujiMiura, AkihitoTsuchida, AtsushiNakano, TohruHasegawa, TakayukiFukuma, KazuakiShimamoto
Journal: Circulation (2000)

Background—Activation of protein kinase C–linked receptors and subsequent opening of the mitochondrial ATP-sensitive K+ (mitoKATP) channel are crucial in preconditioning (PC). This study examined whether postinfarct ventricular remodeling interferes with the PC mechanism. Methods and Results—Two weeks before isolation of hearts, rabbits underwent a sham operation or coronary ligation (COL) to induce remodeling. Isolated buffer-perfused hearts were subjected to 30-minute global ischemia/2-hour reperfusion, and infarct size was expressed as a percentage of the left ventricle (%I/LV), from which the scarred infarct by COL was excluded. Although %I/LV was similar in sham-operated and remodeled hearts (52.9±6.5% versus 45.8±5.2%), PC with 2 episodes of 5-minute ischemia protected sham-operated but not remodeled hearts (%I/LV=18.1±2.5% versus 54.8±2.9%, P<0.05). Infusion of valsartan (10 mg · kg−1 · d−1), an angiotensin II type 1 (AT1) receptor blocker, for 2 weeks after COL prevented the ventricular remodeling...
Local Pulse Pressure and Regression of Arterial Wall Hypertrophy During Long-Term Antihypertensive Treatment
Authors: PierreBoutouyrie, CarolineBussy, DanielHayoz, JurgHengstler, NathalieDartois, BrigitteLaloux, HansBrunner, StéphaneLaurent
Journal: Circulation (2000)

Background—Local pulse pressure (PP) is an independent determinant of carotid artery wall thickness, stronger than mean blood pressure (BP). The present study was designed to assess whether a β-adrenoceptor antagonist–based or an ACE inhibitor–based treatment was able to reduce carotid artery wall hypertrophy through a reduction in carotid PP rather than by lowering mean BP and whether the influence of local PP reduction could also be detected at the site of a muscular artery, the radial artery. Methods and Results—Ninety-eight essential hypertensive patients were randomized to 9 months of double-blind treatment with either celiprolol or enalapril. Arterial parameters were determined with high-resolution echo-tracking systems. PP was measured locally with applanation tonometry and independently of mean BP. After 9 months of treatment, mean BP, carotid PP, and intimal-medial thickness (IMT) decreased significantly, with no difference between the 2 groups. The reduction in carotid PP but not in mean BP was ...
Influence of Sex Difference and Hormones on Elastine and Collagen in the Aorta of Chickens
Authors: Josécembrano, Manuellillo, Joséval, Jorgemardones
Journal: Circulation Research (1960)

Collagen and elastine of the aorta were estimated in normal chickens of both sexes in cockerels, gonadectomized or treated with estradiol, and in hens treated with testosterone. The results showed that collagen and elastine were significantly higher in males than in females. Gonadectomy in males decreased significantly the content of collagen and elastine, so that the values became similar to those observed in females. The treatment of males with estradiol lowered the collagen and elastine content to values similar to those observed in females and in gonadectomized males. The treatment of females with testosterone increased significantly the collagen and elastine content of the aorta to levels similar to those observed in males.
Abstract 023: Development Of Molecular Beacons Targeting Atrial Natriuretic Factor Mrna For Live Cell Sorting
Authors: Brian Wile, Rajneesh Jha, Chunhui Xu, Gang Bao
Journal: Circulation Research (2013)

Introduction: Human embryonic stem cell (hESC) differentiation protocols generate both working and nodal cardiomyocytes, however this mixed cell population is not ideal for clinical applications. No surface markers have been used for the separation of live nodal or working cells to date. Molecular beacons are hairpin oligonucleotide probes with a reporter fluorophore at one end and a quencher at the other; they are designed to fluoresce when hybridized to a complementary target and can be used to detect mRNA in live cells. Atrial natriuretic factor (ANF) is expressed significantly more in working cardiomyocytes than nodal cardiomyocytes. We hypothesize that molecular beacons targeting ANF mRNA may be used to separate working cells from differentiated hESCs. Methods and Results: We designed molecular beacons to target regions of ANF mRNA predicted to be accessible using RNA secondary structure prediction programs. We then developed a positive control cell line using chinese hamster ovary (CHO) cells to select functional beacons. CHO cells were transfected with a plasmid containing the ANF gene and puromycin resistance. Transfected cells were sorted into separate wells and clonal populations were exposed to puromycin for 2 weeks. Surviving colonies were assayed for ANF expression and used as a positive control for beacon characterization. We used this system to screen 10 molecular beacons targeting ANF and found 3 beacons that increased in fluorescence in more than 60% of ANF-CHO cells but less than 5% of untransfected cells. To examine whether molecular beacons are suitable for differentiated cultures, we carried out cardiomyocyte differentiation from hESCs using growth factors. ANF expression was up-regulated in differentiated cultures compared with undifferentiated cells. Transfection of differentiated hESCs using the Neon system was optimized using fluorophore labeled oligonucleotides, a positive control for beacon delivery. Studies are currently underway to determine ANF beacon sensitivity and specificity in hESCs. Conclusions: We have developed several molecular beacons with potential for the use of separating live cells based on the expression of ANF mRNA which could represent a powerful technique for stem cell sorting.
Survey of a Protocol to Increase Appropriate Implementation of Dispatcher-Assisted Cardiopulmonary Resuscitation for Out-of-Hospital Cardiac Arrest
Authors: YoshioTanaka, TaikiNishi, KeikoTakase, YutakaYoshita, YukihiroWato, JunroTaniguchi, YoshitakaHamada, HideoInaba
Journal: Circulation (2014)

Background—Dispatcher-assisted cardiopulmonary resuscitation (DA-CPR) attempts to improve the management of out-of-hospital cardiac arrest by laypersons who are unable to recognize cardiac arrest and are unfamiliar with CPR. Therefore, we investigated the sensitivity and specificity of our new DA-CPR protocol for achieving implementation of bystander CPR in out-of-hospital cardiac arrest victims not already receiving bystander CPR. Methods and Results—Since 2007, we have applied a new DA-CPR protocol that uses supplementary key words. Fire departments prospectively collected baseline data on DA-CPR from January 2009 to December 2011. DA-CPR was attempted in 2747 patients; of these, 417 (15.2%) did not experience cardiac arrest. The sensitivity and specificity of the 2007 protocol versus estimated values of the previous standard protocol were 72.9% versus 50.3% and 99.6% versus 99.8%, respectively. We identified key words that may be useful for detecting out-of-hospital cardiac arrest. Multiple logistic re...
Abstract 3386: The oncogenic role of CD133 in hepatocellular carcinoma
Authors: Yick Pang Ching, Wing Lim Chan
Journal: Cancer Research (2018)

Abstract Liver cancer (hepatocellular carcinoma, HCC) is one of the most prevalent malignancies worldwide. Because of the late diagnosis of the disease, the prognosis of HCC patient is often undesirable. Cancer Stem Cell (CSC), which represents a subpopulation of cancer cells with stem-like properties, plays a critical role in tumorigenesis and contributes significantly to the relapse and chemo-drug resistance of cancers. The cell surface marker, CD133/Prominin-1, has been identified as a biomarker for CSC in various cancers, including HCC. To understand the role of CD133 in hepatocarcinogenesis, we expressed CD133 in HCC cells and showed that CD133 significantly promoted cell growth. Interestingly, our data also indicated that expression of CD133 led to chromosomal instability indicated by elevation of aneuploidy population and centrosome numbers in CD133 expressing cells. To understand the molecular mechanism, we observed that a putative tumour suppressor in HCC, called TAX1-binding protein 2 (TAX1BP2), which functions as a centrosome over-duplication suppresser, was downregulated by CD133. Taken together, these data suggest that CD133 plays an oncogenic role in HCC and may downregulate TAX1BP2 to promote chromosome instability, centrosome duplication and hepatocarcinogenesis. Citation Format: Yick Pang Ching, Wing Lim Chan. The oncogenic role of CD133 in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3386.
Abstract 4326: The chromatin context and consequence of cisplatin-adduct DNA damage
Authors: John Gallon, Erick Loomis, Nicholas Martin, James Flanagan, Robert Brown
Journal: Cancer Research (2018)

Abstract Improvements in survival rates for ovarian cancer lag behind those of other cancers. The combination of paclitaxel and carboplatin, along with debulking surgery, form the primary mode of treatment, however, the majority of patients eventually develop resistance. Epigenetic mechanisms have been implicated in the emergence of drug resistance, with platinum based therapies shown to induce DNA methylation changes at relapse which are associated with overall survival. Using a next generation sequencing approach, including a novel NGS method to map platinum adducts, we sought to investigate the association between platinum-DNA adduct formation and changes to chromatin conformation in the emergence of resistance to platinum therapy. We found chromatin conformation changes at the transcription start sites (TSS) of genes differentially expressed between platinum sensitive and resistant cell lines (p&amp;lt;0.05, n=3 pairs). Furthermore, we found non-TSS associated chromatin conformation changes which distinguish sensitive from resistant lines, and occur primarily in the direction of reduced accessibility in resistant lines (FDR &amp;lt;0.05, log2FC &amp;gt;±1.5). Finally, we found that 2kb windows enriched for platinum-DNA adducts are significantly more accessible than an equal number of random windows on the same chromosome (p&amp;lt;0.05, 1000 permutations). Taken together, these data suggest that platinum treatment may induce epigenetic changes, which reduce chromatin accessibility, rendering cells less susceptible to the formation of platinum-DNA adducts in subsequent treatments, resulting in cells becoming less sensitive to the drug. Citation Format: John Gallon, Erick Loomis, Nicholas Martin, James Flanagan, Robert Brown. The chromatin context and consequence of cisplatin-adduct DNA damage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4326.
Bimodal Distribution of Angiographic Measures of Restenosis Six Months After Coronary Stent Placement
Authors: AlbertSchömig, AdnanKastrati, ShpendElezi, HelmutSchühlen, JosefDirschinger, FelixDannegger, ManfredWilhelm, KurtUlm
Journal: Circulation (1997)

Background Restenosis has been perceived as the tail end of a normal distribution of the response of the vessel to the intervention. However, recent studies have described a bimodal distribution for de novo lesions after percutaneous transluminal coronary angioplasty. This finding suggests that some lesions may be more susceptible for restenosis. Whether this holds true for a wider spectrum of lesions undergoing stent placement is not yet known. The present study analyzes the frequency distribution of angiographic indexes of restenosis 6 months after coronary stent implantation. Methods and Results Quantitative angiographic evaluation was performed in 1084 lesions of 1084 patients before, immediately after, and 6 months after successful Palmaz-Schatz stent placement; this represented 80.4% of patients eligible for follow-up angiography. Principal end points of the analysis were angiographic indexes of restenosis at 6 months. Twenty-two lesions that became totally occluded at follow-up were excluded from m...
Abstract 597: Lung tumor histology as prognostic factor for short-term postoperative outcomes
Authors: Roger Gerard, Frank Velez-Cubian, Carla Moodie, Joseph Garrett, Jacques Fontaine, Eric Toloza
Journal: Cancer Research (2018)

Abstract Introduction: Based on the 2015 World Health Organization (WHO) Classification of Lung Tumors, we sought to investigate the relationship of common lung tumor histologies and their utility as prognostic clinical correlates of short-term perioperative outcomes. Methods: We retrospectively analyzed patients who underwent robotic-assisted video-thoracoscopic lobectomy by one surgeon over 81 months. Patients were grouped based on tumor histology on their final surgical pathology report. Patients' demographics, smoking history, lobar distribution, extent of resection, intraoperative outcomes, perioperative complications, and hospital length of stay were compared among the groups. Results: Among 420 study patients, the most common tumor type was adenocarcinoma (AD, 59.8%), followed by squamous cell carcinoma (SQ, 19.3%) and neuroendocrine carcinoma (NEC, 11.7%). Final histology for the remainder of the cohort consisted of adenosquamous carcinoma (AdSq, 2.1%) and pulmonary metastasis (7.1%). All patients with AdSq tumor histology had a positive smoking history, which was a significantly higher proportion than for those with NEC tumor type (100% vs 71.4%; p&amp;lt;0.001). Those with AdSq tumor histology were both significantly older and developed significantly larger tumors by time of resection (p&amp;lt;0.001 and p=0.003, respectively). Patients with AdSq tumors required more extensive resections compared to the remaining groups (p&amp;lt;0.004). They also experienced significantly greater estimated blood loss (EBL) and significantly longer operative times (p=0.005 and p=0.018, respectively) than the remaining groups. Patients with SQ or pulmonary metastasis had slightly more postoperative complications, but this was not statistically significant (p=0.990). Conclusion: Patients with AdSq histology type were older and had larger tumors, which put them at risk of intraoperative difficulties, with more extensive resections, longer operative times, and greater EBL. Despite this, AdSq histology did not affect the postoperative course. Citation Format: Roger Gerard, Frank Velez-Cubian, Carla Moodie, Joseph Garrett, Jacques Fontaine, Eric Toloza. Lung tumor histology as prognostic factor for short-term postoperative outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 597.
Intracoronary 99mTc-Sestamibi Single Photon Emission Computed Tomography/Computed Tomography for Preoperative Evaluation of At-Risk Myocardium
Authors: DavidPattison, JamesWestcott, AndrewAjani, PhillipAntippa, SubodhJoshi, ElaineLui, FrancescaLangenberg, NathanBetter
Journal: Circulation (2013)
Abstract 4638: Predictive computational approaches to guide the covalent targeting of cysteine residues in drug discovery
Authors: Richard A. Ward, Richard Lonsdale
Journal: Cancer Research (2018)

Abstract Targeted covalent inhibition is an established approach for increasing the potency and selectivity of potential drug candidates, and has also been used to identify tool compounds for target validation studies. It is evident that binding to reversible recognition elements within the pocket is essential for selective covalent inhibition, but this must also be achieved with the appropriate level of inherent reactivity of the covalent functionality and compatible geometry and reactivity of the target amino acid. We have assessed the ability of several experimental and computational approaches to predict the intrinsic reactivity of a range of cysteine targeting warheads, some of which can be used in prospective compound design. In addition, molecular dynamics (MD) simulations in combination with pKa prediction methods have been used to investigate the accessibility and potential reactivity of target cysteines towards covalent inhibition. As part of this work a number of case studies will be reported including retrospective examples from covalent drug discovery efforts along with prospective use towards novel targets. Finally, a dataset of osimertinib analogues along with other EGFR inhibitors of varying reactivity will be discussed to enable further insight into the impact of reversible and covalent interactions on inhibitor binding. Citation Format: Richard A. Ward, Richard Lonsdale. Predictive computational approaches to guide the covalent targeting of cysteine residues in drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4638.
Glycan Masking Focuses Immune Responses to the HIV-1 CD4-Binding Site and Enhances Elicitation of VRC01-Class Precursor Antibodies
Authors: Hongying Duan, Xuejun Chen, Jeffrey C. Boyington, Cheng Cheng, Yi Zhang, Alexander J. Jafari, Tyler Stephens, Yaroslav Tsybovsky, Oleksandr Kalyuzhniy, Peng Zhao, Sergey Menis, Martha C. Nason, Erica Normandin, Maryam Mukhamedova, Brandon J. DeKosky, Lance Wells, William R. Schief, Ming Tian, Frederick W. Alt, Peter D. Kwong, John R. Mascola
Journal: Immunity (2018)
Most GP trainees intend to work less than full time, survey shows
Authors: Abi Rimmer
Journal: BMJ (2018)

The vast majority of GP trainees do not intend to work full time in clinical practice once they have qualified, a survey has found.

The survey of 729 trainees, conducted by the King’s Fund,1 found that 21.7% intended to be working full time a year after they qualified, compared with 46.9% who intended to work part time. Just 7.4% of trainees said that they would work full time in clinical practice five years after they had qualified, and …
Active State in the Smooth Muscle of the Rat Portal Vein in Relation to Electrical Activity and Isometric Force
Authors: Börjejohansson
Journal: Circulation Research (1973)

Contractile activity in smooth muscle is usually too variable to permit a meaningful analysis of the time course of the active state. A regular activity of uniform contractions was obtained in the present experiments on isolated rat portal veins by simultaneous increases in the external potassium and calcium concentrations. The contractions were associated with electrical discharges which lasted between 0.8 and 1.5 seconds. The active state during these uniform contractions was determined from the shortening velocities after isotonic releases and from the redevelopment of tension after controlled releases. Results obtained with the two methods agreed satisfactorily. The active state increased over the first 0.4-0.6 seconds. Suggestive evidence of a plateau phase was found in some experiments. The active state clearly began to fall about 1 second after the start of the contraction, and this fall coincided with the fall in the first time derivative of isometric force (dP/dt). The maximal intensity of the ac...