tbuckley/cabot-search huggingface dataset:
Abstract 1022: The role of dopamine signaling in prostate cancer disparities
Authors: Isaiah R. Pickett, Ava M. Boston, Marwah M. Almathkour, Camille Ragin, Mehmet A. Bilen, Adeboye O. Osunkoya, Bekir Cinar
Journal: Cancer Research (2019)

Abstract Prostate cancer is the second leading cause of cancer-related deaths among men in western countries. Majority of prostate tumors often evolves as metastatic castration-resistant prostate cancer (CRPC) following hormonal therapy. Metastatic prostate cancer is the major cause of mortalities from this disease. African-American (AA) men have the highest incidence and mortality rate compared to any other race such as Caucasian American (CA). Despite recent advances, the cellular and molecular mechanisms that contribute to this disparity are unknown, obstructing the development of an effective therapy for this disease. Genetic and epigenetic studies have indicated that the biology of prostate cancer in AA men is substantially different from CA. Here, we investigate the dopamine (DA) signaling to better understand the mechanism of prostate cancer disparity. Our analysis of the prostate cancer public data sets showed that the dopamine receptor (DR) genes were amplified in up to 18% prostate cancer clinical cases. We have demonstrated that the levels of DR transcripts were significantly higher in the metastatic prostate cancer cell lines with African genetic ancestry than CA counters. We also demonstrate that the efficacy of pimozide, a potent DRD inhibitor and an FDA-approved antipsychotic, on AA cells was significantly higher than CA cells. In addition, we have found that L-dopa, an immediate precursor of DA differentially regulates the growth of AA and CA prostate cancer cells in a dose dependent manner. We also found that carbidopa, a potent inhibitor of the dopa decarboxylase, suppressed prostate cancer cell growth by L-dopa and showed that carbidopa re-sensitized CRPC cell line to enzalutamide, a potent inhibitor of androgen receptor (AR) signaling. These observations suggest that DA/DR signaling plays a critical role in prostate cancer disparity, making the DA/DR-AR axis a viable therapeutic target to reduce disparities in cancer mortality. Citation Format: Isaiah R. Pickett, Ava M. Boston, Marwah M. Almathkour, Camille Ragin, Mehmet A. Bilen, Adeboye O. Osunkoya, Bekir Cinar. The role of dopamine signaling in prostate cancer disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1022.
Echocardiographic assessment of left ventricular function in aortic valve disease.
Authors: I GMcDonald
Journal: Circulation (1976)

Echocardiography was used to study left ventricular size and contraction in 128 patients with isolated aortic valve disease -45 patients with aortic stenosis, 25 with mixed aortic valve disease and 58 with aortic regurgitation. Left ventricular measurements included the end-diastolic internal dimension (LVIDd), mural thickness (PWTd), an index of circumferential myocardial contraction-fractional shortening (FS=[(LVIDd-LVIDs)/LVIDd] X 100)--and stroke volume (LVSV). In the absence of left ventricular failure, measurements in aortic stenosis were characteristic of pressure overload with normal LVIDd and FS and an increase in PWTd related to the severity of stenosis; in aortic regurgitation, there was volume overload with increases in LVIDd and PWTd which were related to the severity of regurgitation, while FS was slightly reduced. In mixed aortic valve disease there was evidence of both pressure and volume overload. When left ventricular failure was associated with aortic stenosis, mixed aortic valve diseas...
Large granular lymphocytic leukemia – A retrospective study of 319 cases
Authors: Ning Dong, Franco Castillo Tokumori, Leidy Isenalumhe, Yumeng Zhang, Ankita Tandon, Todd C. Knepper, Qianxing Mo, Haipeng Shao, Ling Zhang, Lubomir Sokol
Journal: American Journal of Hematology (2021)

Abstract Large granular lymphocytic leukemia (LGLL) is a rare hematological malignancy that arises from cytotoxic T lymphocytes (T‐LGLL) in 85% of cases and natural killer (NK) cells in the rest. A significant knowledge gap exists regarding the pathogenesis, treatment choices, and prognostic factors of LGLL. We report a cohort of 319 consecutive LGLL patients who presented to our cancer center between 2001 and 2020. A total of 295 patients with T‐LGLL and 24 with chronic NK‐cell lymphoproliferative disorder (CLPD‐NK) were identified. The median age was 65 years (range, 17–90 years). Eighty‐three patients (26.0%) had autoimmune diseases. A total of 119 patients (37.3%) had coexisting malignancies, 66 (20.7%) had solid tumors, and 59 (18.5%) had hematological malignancies. Most coexisting malignancies were diagnosed before the diagnosis of LGLL. Treatment was needed for 57% of patients. Methotrexate (MTX), cyclophosphamide (Cy), and cyclosporine A (CSA) were most used and had similar response rates between 61.5%–74.4%. Cy produced more complete responses (32.3%) compared to MTX and CSA (15.7% and 23.1%, respectively). Thrombocytopenia, splenomegaly, and female gender (after controlling for autoimmune diseases) were associated with decreased response rates to MTX, CSA, or Cy. Autoimmune diseases were associated with increased response rates. Thrombocytopenia was an independent risk factor for worse survival.
The Impact of Migration on the Gut Metagenome of South Asian Canadians
Authors: Julia K. Copeland, Gary Chao, Shelley Vanderhout, Erica Acton, Pauline W. Wang, Eric I. Benchimol, Ahmed El-Sohemy, Ken Croitoru, Jennifer L. Gommerman, David S. Guttman
Journal: Gut Microbes (2021)

South Asian (SA) Canadian immigrants have a higher risk of developing certain immune-mediated inflammatory diseases compared to non-migrant SAs. We sought to investigate the effect of migration on the gut metagenome and to identify microbiological associations between migration and conditions that may influence the development of immune-mediated inflammatory diseases. Metagenomic analysis of 58 first-generation (GEN1) SA immigrants and 38 unrelated Canadian born children-of-immigrants (GEN2) determined that the time lived in Canada was associated with continued changes in gut microbial communities. Migration of GEN1 to Canada early in life results in a gut community with similarities to GEN2 SA Canadians and non-SA North Americans. Conversely, GEN1 immigrants who arrived recently to Canada exhibited pronounced differences from GEN2, while displaying microbial similarities to a non-migrating SA cohort. Multivariate analysis identified that community composition was primarily influenced by high abundance taxa. Prevotella copri dominated in GEN1 and non-migrant SAs. Clostridia and functionally related Bacteroidia spp. replaced P. copri dominance over generations in Canada. Mutually exclusive Dialister species occurred at differing relative abundances over time and generations in Canada. This shift in species composition is accompanied by a change in genes associated with carbohydrate utilization and short-chain fatty acid production. Total energy derived from carbohydrates compared to protein consumption was significantly higher for GEN1 recent immigrants, which may influence the functional requirements of the gut community. This study demonstrates the associations between migration and the gut microbiome, which may be further associated with the altered risk of immune-mediated inflammatory diseases observed for SA Canadians.
Inhibition of nitric oxide formation in the nucleus tractus solitarius increases renal sympathetic nerve activity in rabbits.
Authors: SHarada, STokunaga, MMomohara, HMasaki, TTagawa, TImaizumi, ATakeshita
Journal: Circulation Research (1993)

It has been shown that nitric oxide (NO) is synthesized in the central nervous system as well as in vascular endothelial cells. However, the physiological role of NO in cardiovascular regulation by the central nervous system remains unclear. This objective of this study was to examine the possibility that NO plays a role in neural transmission in the nucleus tractus solitarius (NTS) and thus contributes to control of sympathetic nerve activity in rabbits. We examined the effects of NG-monomethyl-L-arginine (L-NMMA), an inhibitor of the formation of NO from L-arginine, microinjected into the NTS on arterial pressure (AP), heart rate (HR), and renal sympathetic nerve activity (RSNA). L-NMMA increased AP and RSNA in rabbits with intact as well as denervated sinoaortic baroreceptors and vagi. L-NMMA increased HR only in rabbits with sinoaortic denervation and vagotomy. Pretreatment with L-arginine microinjected into the NTS, which did not alter baseline AP, HR, and RSNA, prevented the increases in AP and RSNA...
ACE2 expression is regulated by AhR in SARS-CoV-2-infected macaques
Authors: Jiadi Lv, Pin Yu, Zhenfeng Wang, Wei Deng, Linlin Bao, Jiangning Liu, Fengli Li, Qiangqiang Zhu, Nannan Zhou, Qi Lv, Guanpeng Wang, Shunyi Wang, Yabo Zhou, Jiangping Song, Wei-Min Tong, Yuying Liu, Chuan Qin, Bo Huang
Journal: Cellular and Molecular Immunology (2021)
Effects of chronic progressive myocardial hypertrophy on indexes of cardiac autonomic innervation.
Authors: KLindpaintner, D DLund, P GSchmid
Journal: Circulation Research (1987)

The development of cardiac hypertrophy is associated with marked changes in cardiac autonomic innervation. Significant and sustained reductions of myocardial catecholamine stores and activities of tyrosine hydroxylase and dopamine beta-hydroxylase have been reported in models of acutely induced ventricular hypertrophy. Conversely, activity of choline acetyltransferase, a marker of parasympathetic nervous function, shows transient increases during the development of acute right ventricular hypertrophy. The potential physiological importance of these changes prompted us to examine a clinically more relevant model of slowly progressive ventricular hypertrophy. Application of a loose band around the pulmonary artery of weanling guinea pigs resulted in a growth-related progressive right ventricular pressure overload. Right ventricular weight-to-body-weight ratio was increased significantly and progressively at 9 and 18 weeks in banded animals (0.92 +/- 0.05 and 1.31 +/- 0.11 mg/g, respectively, p less than 0.0...
SerpinB13 antibodies promote β cell development and resistance to type 1 diabetes
Authors: Yury Kryvalap, Matthew L. Jiang, Nadzeya Kryvalap, Cole Hendrickson, Jan Czyzyk
Journal: Science Translational Medicine (2021)

Pancreatic endocrine cell development is dependent on the rescue of the neurogenin3 (Ngn3) transcription factor from repression by Notch. The signals that prevent Notch signaling, thereby allowing the formation of pancreatic endocrine cells, remain unclear. We show that inhibiting serpinB13, a cathepsin L (CatL) protease inhibitor expressed in the pancreatic epithelium, caused in vitro and in vivo cleavage of the extracellular domain of Notch1. This was followed by a twofold increase in the Ngn3+ progenitor cell population and enhanced conversion of these cells to express insulin. Conversely, both recombinant serpinB13 protein and CatL deficiency down-regulated pancreatic Ngn3+ cell output. Mouse embryonic exposure to inhibitory anti-serpinB13 antibody resulted in increased islet cell mass and improved outcomes in streptozotocin-induced diabetes at 8 weeks of age. Moreover, anti-serpinB13 autoantibodies stimulated Ngn3+ endocrine progenitor formation in the pancreas and were associated with delayed progression to type 1 diabetes (T1D) in children. These data demonstrate long-term impact of serpinB13 activity on islet biology and suggest that promoting protease activity by blocking this serpin may have prophylactic potential in T1D.
Influence of cardiac fiber orientation on wavefront voltage, conduction velocity, and tissue resistivity in the dog.
Authors: D ERoberts, L THersh, A MScher
Journal: Circulation Research (1979)

When the canine epicardium is stimulated, the spread of epicardial excitation is 2.4 times faster parallel to the long axes of the cardiac fibers than perpendicular to them. Likewise, gross tissue resistivity is lower parallel to fibers by a factor of 3.2, and the voltage across the depolarization wave is approximately three times as great in the longitudinal direction. Equations are presented which relate these variables. Theoretical considerations confirm the experimental finding that the potentials around a wave of depolarization cannot be accounted for by the conventional hypothesis that the wavefront is a uniform double-layer current source.
Strategies to overcome drug resistance using SHP2 inhibitors
Authors: Meng Liu, Shan Gao, Reham M. Elhassan, Xuben Hou, Hao Fang
Journal: Acta Pharmaceutica Sinica B (2021)

Encoded by PTPN11, the SHP2 (Src homology-2 domain-containing protein tyrosine phosphatase-2) is widely recognized as a carcinogenic phosphatase. As a promising anti-cancer drug target, SHP2 regulates many signaling pathways such as RAS-RAF-ERK, PI3K-AKT and JAK-STAT. Meanwhile, SHP2 plays a significant role in regulating immune cell function in the tumor microenvironment. Heretofore, five SHP2 allosteric inhibitors have been recruited in clinical studies for the treatment of cancer. Most recently, studies have proved the therapeutic potential of SHP2 inhibitor in overcoming drug resistance of kinase inhibitors and programmed cell death-1 (PD-1) blockade. Herein, we review the structure, function and small molecular inhibitors of SHP2, and highlight recent progress in overcoming drug resistance using SHP2 inhibitor. We hope this review would facilitate the future clinical development of SHP2 inhibitors.
Chloride dependence of pH modulation by beta-adrenergic agonist in rat cardiomyocytes.
Authors: MDésilets, MPucéat, GVassort
Journal: Circulation Research (1994)

The effects of beta-adrenergic agonists on pHi were studied on single ventricular myocytes isolated from adult rat heart and loaded with the acetoxymethyl ester (AM) form of the pH indicator SNARF-1. In modified Krebs' solution containing 20 mmol/L HEPES and 4.4 mmol/L HCO3-, isoproterenol (1 mumol/L) caused a significant decrease of steady-state pHi from 7.20 +/- 0.02 to 7.13 +/- 0.02 (mean +/- SEM) within 2 minutes. This acidification, which was also observed in myocytes that were preloaded with the Ca2+ chelator BAPTA and superfused with nominally Ca(2+)-free solution, was blocked by propranolol as well as by the specific beta 1-antagonist CGP 20712 A but not by the beta 2-antagonist ICI 118,551. Forskolin (10 mumol/L) induced a similar reversible decrease of pHi (average decrease, 0.11 +/- 0.02 pH unit). Furthermore, adenosine (100 mumol/L) substantially attenuated the isoproterenol-induced decrease of pHi. The effect of isoproterenol was not prevented by inhibitors of the Na(+)-H+ antiport, amiloride...
Catecholamines can induce adenosine receptor-mediated protection of the myocardium but do not participate in ischemic preconditioning in the rabbit.
Authors: J DThornton, J FDaly, M VCohen, X MYang, J MDowney
Journal: Circulation Research (1993)

The role of catecholamines in ischemic preconditioning is unclear. Accordingly, the effects of tyramine-induced norepinephrine release and alpha 1-receptor blockade were examined. Ischemic preconditioning with a 5-minute coronary occlusion 10 minutes before a 30-minute ischemic interval resulted in only 7.7 +/- 3.1% infarction of the risk area, significantly less than that in control rabbits with isolated 30-minute coronary occlusions (34.4 +/- 3.2%, P < .01). Intravenous infusion of tyramine 10 minutes before 30 minutes of ischemia also protected the heart from infarction to an extent similar to that seen with ischemic preconditioning (6.9 +/- 2.4% infarction). This protection observed with tyramine infusion was eliminated by alpha 1-receptor blockade with BE 2254 (36.8 +/- 2.6% infarction) but was unaffected by beta-blockade with propranolol (10.5 +/- 2.4% infarction). Furthermore, the protection was unaffected when the tyramine-induced hypertension was attenuated by allowing blood to flow into a volume...
Identification of a specific radioligand for the cardiac rapidly activating delayed rectifier K+ channel.
Authors: C CChadwick, A MEzrin, BO'Connor, W AVolberg, D ISmith, K JWedge, R JHill, G MBriggs, E DPagani, P JSilver
Journal: Circulation Research (1993)

Class III antiarrhythmic drugs show promise as effective treatments for the suppression of potentially lethal cardiac arrhythmias. Dofetilide (UK-68,798), is a potent class III antiarrhythmic agent that is presently under clinical investigation. The objective of this study was to determine whether [3H]dofetilide could be used as a specific radioligand for the rapidly activating delayed rectifier K+ channel of the heart. We find that [3H]dofetilide binds to high-affinity sites on guinea pig cardiac myocytes. Competition studies using unlabeled dofetilide indicate that binding is characterized by an IC50 of 100 +/- 30 nM (mean +/- SD, n = 13). Scatchard analyses of binding indicate a Kd of 70 +/- 6 nM and a maximal binding capacity of 0.30 +/- 0.02 pmol/mg protein. [3H]Dofetilide is displaced from guinea pig myocytes by dofetilide, clofilium, quinidine, sotalol, and sematilide with a rank order of potency that correlates with functional blockade of the rapidly activating delayed rectifier K+ current (correl...
Regional ejection fraction: a quantative radionuclide index of regional left ventricular performance.
Authors: D EMaddox, JWynne, RUren, J AParker, JIdoine, L CSiegel, J MNeill, P FCohn, B LHolman
Journal: Circulation (1979)

Radionuclide measurements of regional left ventricular ejection fraction were evaluated as a quantitative index of regional left ventricular function. Left ventricular regional ejection fractions were derived from background-corrected, time-activity curves in 43 patients assessed by both gated equilibrium radionuclide angiocardiography and left ventricular contrast angiography. From a single, modified left anterior oblique projection, the regional change in background corrected counts was determined in each of three anatomic regions. The normal range for regional radionuclide ejection fraction was determined in 10 patients with normal contrast ventriculograms and without obstructive coronary artery disease at coronary arteriography. Regional ejection fraction was compared with percent segmental axis shortening and extent of akinetic segments in corresponding regions of the contrast ventriculogram. Radionuclide and roentgenographic methods were in agreement as to the presence or absence of abnormal wall mo...
The use of Doppler flow velocity measurement to assess the hemodynamic response to vasodilators in patients with heart failure.
Authors: UElkayam, J MGardin, RBerkley, C AHughes, W LHenry
Journal: Circulation (1983)

To determine if the hemodynamic response to vasodilator therapy can be assessed noninvasively by pulsed Doppler velocimetry, we compared the hemodynamic changes after treatment to changes in Doppler aortic blood flow measurements. The relationship between the absolute values and percent changes of invasively measured systemic vascular resistance (SVR) and stroke volume (SV) and Doppler-measured peak flow velocity (PFV), left ventricular ejection time (ET) and flow velocity integral (FVI) were evaluated. Measurements were made during 18 drug interventions in 13 patients treated with vasodilator agents for congestive heart failure (CHF). A poor correlation was found between the absolute values of either SVR or SV and the absolute values of each of the three Doppler aortic blood flow indexes studied. In contrast, a good correlation was found between percent changes in aortic PFV and in SVR (r = -0.89), and between percent changes in Doppler aortic FVI and in SV (r = 0.88). The correlation between percent cha...
Modulation by prostaglandin synthesis inhibitors of the action of exogenous angiotensin II on glomerular ultrafiltration in the rat.
Authors: CBaylis, B MBrenner
Journal: Circulation Research (1978)

We studied the effects of angiotensin II (A II) infusion, with and without inhibition of prostaglandin (PG) synthesis, on the determinants of glomerular ultrafiltration in 27 plasma volume-expanded Munich-Wistar rats. The effects of PG inhibition alone and infusion of vehicle alone also were investigated. With a pressor dose of A II single nephron (SN) GFR and total GFR did not change significantly, despite declines in both glomerular plasma flow rate (QA) and the ultrafiltration coefficient (Kf), due to an offsetting rise in the transcapillary hydraulic pressure difference (deltaP). Afferent and efferent arteriolar resistances (RA and RE) increased by approximately 100% above control during A II infusion. Inhibition of PG synthesis alone and infusion of vehicle alone similarly failed to affect SNGFR and total GFR, and only slight changes occurred in the determinants of glomerular ultrafiltration in these rats. When A II infusion was accompanied by inhibition of PG synthesis, however, profound declines in...
Jim Dornan: senior vice president of the Royal College of Obstetricians and Gynaecologists and Northern Ireland’s pre-eminent obstetrician for four decades
Authors: Penny Warren
Journal: BMJ (2021)

Photo credit: Jess Dornan-Lynas

Talking to his houseman on a plane flying home, Harith Lamki suggested the young man make a career in obstetrics and gynaecology. Jim Dornan took the advice and, Lamki says, “The rest is history. He bloomed!”

Dornan was chair of fetal medicine at Queen’s University Belfast; he set up the research charity Northern Ireland Mother and Baby Appeal (NIMBA, now TinyLife); and was a leading figure at the Royal College of Obstetricians and Gynaecologists. In a stellar career spanning four decades, his research into detecting high risk babies in low risk mothers helped change the landscape of obstetrics, saving many babies from stillbirth. Dornan said, “When we formed NIMBA in 1988 the perinatal mortality rate was 30 per 1000. Our role used to be like that of firemen. Now, given how much we know about the baby before birth, we’re more like fire prevention officers.”

Dornan was born in Holywood, County Down. His father—also Jim—was the general manager of the Incorporated Cripples Institutes (now HarmonI), where the family lived and …
The value of lesion cross-sectional area determined by quantitative coronary angiography in assessing the physiologic significance of proximal left anterior descending coronary arterial stenoses.
Authors: D GHarrison, C WWhite, L FHiratzka, D BDoty, D HBarnes, C LEastham, M LMarcus
Journal: Circulation (1984)

The results of previous work from this laboratory have shown a poor correlation between percent stenosis (determined visually with calipers) and the coronary reactive hyperemic response (an index of maximal coronary vasodilator capacity) determined during cardiac surgery. This study was performed to determine whether other parameters of lesion severity could predict the reactive hyperemic response and thus the hemodynamic significance of coronary stenoses in human beings. Twenty-three patients with lesions in the proximal left anterior descending coronary artery were studied. To account for differences in expected vessel size, patients with large diagonal branches (greater than one-half the diameter of the left anterior descending artery) arising before the lesion were excluded. Computer-assisted quantitative coronary angiography was used to measure percent diameter stenosis, percent area stenosis, and minimal stenosis cross-sectional area. With a pulsed Doppler velocity probe, reactive hyperemic response...