bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigallocatechin-3-gallate induces apoptosis in estrogen receptor–negative human breast carcinoma cells via modulation in protein expression of p53 and Bax and caspase-3 activation
Authors: Roy Anshu M. , Baliga Manjeshwar S. , Katiyar Santosh K. 
Published: June 2022

Abstract
Epigallocatechin-3-gallate (EGCG) has been shown to have anticarcinogenic effects in in vitro and in vivo models, and this effect is mediated at least in part by its ability to induce apoptosis in cancer cells without affecting normal cells. It has been recognized that estrogen receptor (ER)–dependent breast cancers generally have a better prognosis and are often responsive to antiestrogen therapy; however, ER-independent breast cancers are more aggressive and unresponsive to antiestrogens. Using the MDA-MB-468 human breast cancer cell line as an in vitro model of ER-negative breast cancers, we found that treatment of EGCG resulted in dose-dependent (5-80 μg/mL) and time-dependent (24-72 hours) inhibition of cellular proliferation (15-100%) and cell viability (3-78%) in MDA-MB-468 cells. Decrease in cell viability was associated with the induction of apoptosis (18-66%) which was analyzed by DNA ladder assay, fluorescence staining, and flow cytometry. Induction of apoptosis by EGCG could be corroborated to the increased expression of tumor suppressor protein p53 and its phosphorylation at Ser 15 residue. EGCG decreased the expression of antiapoptotic protein Bcl-2 but increased proapoptotic protein Bax in these cells. The increased ratio of Bax/Bcl-2 proteins after EGCG treatment may have resulted in increased release of cytochrome c from mitochondria into cytosols, increased expression of Apaf-1, and activation of caspase-3 and poly(ADP-ribose) polymerase, which may lead to apoptosis in MDA-MB-468 cells. Together, the results of this study provide evidence that EGCG possesses anticarcinogenic effect against ER-negative breast cancer cells and thus provide the molecular basis for the future development of EGCG as a novel and pharmacologically safe chemopreventive agent for breast cancer prevention.
Inhibition of ABCB1 (MDR1) and ABCB4 (MDR3) expression by small interfering RNA and reversal of paclitaxel resistance in human ovarian cancer cells
Authors: Duan Zhenfeng , Brakora Katherine A. , Seiden Michael V. 
Published: June 2022

Abstract
Ovarian cancer is currently the most lethal gynecologic malignancy in developed countries, and paclitaxel is a cornerstone in the treatment of this malignancy. Unfortunately, the efficacy of paclitaxel is limited by the development of drug resistance. Clinical paclitaxel resistance is often associated with ABCB1 (MDR1) overexpression, and in vitro paclitaxel resistance typically demonstrates overexpression of the ABCB1 gene. In this study, we demonstrate that paclitaxel-resistant cell lines overexpress both ABCB1 and ABCB4 (MDR3). To evaluate the role of these transporters in paclitaxel-resistant ovarian cancer cells, small interference RNAs (siRNAs) were used to target ABCB1 and ABCB4 RNA in the paclitaxel-resistant SKOV-3TR and OVCAR8TR ovarian cancer cell lines. Treatment of these lines with either chemically synthesized siRNAs or transfection with specific vectors that express targeted siRNAs demonstrated decreased mRNA and protein levels of ABCB1 or ABCB4. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays of siRNA-treated cells demonstrated 7- to 12.4-fold reduction of paclitaxel resistance in the lines treated with the synthesized siRNA of ABCB1 and 4.7- to 7.3-fold reduction of paclitaxel resistance in the cell lines transfected with siRNA of ABCB1 expressing vectors. ABCB4 siRNA-treated cell lines showed minor reduction in paclitaxel resistance. These results indicate that siRNA targeted to ABCB1 can sensitize paclitaxel-resistant ovarian cancer cells in vitro and suggest that siRNA treatment may represent a new approach for the treatment of ABCB1-mediated drug resistance.
Quantitative analysis of p53-targeted gene expression and visualization of p53 transcriptional activity following intratumoral administration of adenoviral p53 in vivo
Authors: Ohtani Shoichiro , Kagawa Shunsuke , Tango Yasuhisa , Umeoka Tatsuo , Tokunaga Naoyuki , Tsunemitsu Yousuke , Roth Jack A. , Taya Yoichi , Tanaka Noriaki , Fujiwara Toshiyoshi 
Published: June 2022

Abstract
To analyze the mechanism of the antitumor effect of an adenoviral vector expressing the p53 tumor suppressor (Ad-p53) in vivo, we quantitatively assessed p53-targeted gene expression and visualized transcriptional activity of p53 in tumors in nude mice treated with Ad-p53. Human lung cancer (H1299) xenografts established in nude mice were treated by intratumoral administration of Ad-p53. The levels of expression of exogenous p53 and p53-targeted genes p21, MDM2, Noxa, and p53AIP1 were quantified by real-time reverse transcription-PCR (RT-PCR) and induction of apoptosis was observed histochemically on days 1–3, 7, and 14 after treatment. Expression of mRNA of exogenous p53 and p53-targeted genes (except p53AIP1) was at its maximum 1 day after Ad-p53 treatment and then decreased rapidly; apoptosis was evident in situ 2–3 days after treatment. We developed a noninvasive and simple method for monitoring the transcriptional activity of exogenous p53 following intratumoral administration of Ad-p53 in nude mice. We established H1299 cells that express the green fluorescent protein (GFP) reporter gene under the control of p53-responsive p21 promoter (i.e., the p53R-GFP reporter system). Xenografts of these cells in nude mice were treated by intratumoral administration of Ad-p53, and the transcriptional activity of exogenous p53 could be visualized as intratumoral GFP expression in real time by 3-CCD camera. Expression of GFP was maximal 3 days after treatment and decreased remarkably by 7 days after treatment. We demonstrated that Ad-p53 treatment rapidly induced p53-targeted genes and apoptosis in tumors and succeeded in visualizing p53 transcriptional activity in vivo. We also found that Ad-p53 infection induced phosphorylation of p53 at Ser46 in p53-sensitive H1299 cells in vitro but not in p53-resistant H226Br cells, suggesting that phosphorylation of Ser46 is involved in p53-dependent apoptosis. Our data indicate that quantitative analysis of p53-targeted gene expression by real-time quantitative RT-PCR and visualization of p53 transcriptional activity in fresh xenografts by using the p53R-GFP reporter system may be useful in assessing the mechanisms of the antitumor effects of Ad-p53 and novel therapeutic approaches.
Abstract A04: Geographic and socioeconomic disparities in exposure to carcinogenic air toxics in St. Louis, Missouri
Authors: Ekenga Christine , Yeung Cheuk Yui , Oka Masayoshi 
Published: June 2022

Abstract
Background: Residential segregation has been associated with exposure to hazardous air pollutants in the United States. However, few studies have utilized spatial approaches for measuring segregation at the neighborhood level. We used spatial epidemiologic methods to examine associations between neighborhood characteristics and exposure to carcinogenic air toxics in St. Louis, Missouri.
Methods: We obtained cancer risk data from the United States Environmental Protection Agency’s 2011 National Air Toxics Assessment and used a geographic information system to identify air toxic hotspots in the St. Louis region. Census tract-level data from 2010 to 2014 from the American Community Survey were used to develop isolation measures that capture spatial patterns of residential segregation within the St. Louis region. In the current analysis, we developed a black isolation measure and a poverty isolation measure as indicators of spatial separation from other racial/ethnic populations and from nonpoverty populations, respectively. Relative risks were used to evaluate relationships between neighborhood characteristics and air toxic hotspots.
Results: The distribution of carcinogenic air toxics varied throughout the St. Louis region and clustered near interstate highways. Neighborhood-level measures of the racial and economic isolation were associated with air toxic hotspots. Census tracts in the highest quartile of black isolation were eight times more likely to be located in an air toxic hotspot than tracts in the lowest quartile (RR = 8.1, 95% Confidence Interval = 5.9-12.1). Census tracts in the highest quartile of economic isolation were five times more likely to be located in an air toxic hotspot than tracts in the lowest quartile (RR = 5.0 95% Confidence Interval = 3.3-9.4).
Conclusions: There are geographic and socioeconomic disparities in exposure to carcinogenic air toxics in the St. Louis region. The identification of local air toxic hotspots can inform public health efforts to eliminate disparities in exposure to air toxics.
Citation Format: Christine Ekenga, Cheuk Yui Yeung, Masayoshi Oka. Geographic and socioeconomic disparities in exposure to carcinogenic air toxics in St. Louis, Missouri [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A04.
Abstract IA06: Mutational signatures of environmental carcinogens in mouse and human cancers
Authors: Balmain Allan 
Published: June 2022

Abstract
Mouse models of cancer have been instrumental in the development of our understanding of the processes that drive multistage carcinogenesis from the initiation stage to metastasis. Tumors induced in mice by exposure to carcinogenic chemicals replicate many of the biologic and genetic features of multistage cancer in human populations. Skin and lung tumors initiated by chemical mutagens generally have carcinogen-specific mutations in Hras and Kras, respectively. However, these mutation patterns are seen not only in the target Ras genes, but also can be detected genome-wide as “mutational signatures” that are diagnostic for each carcinogen. We have extended this concept to search for new mutation signatures in tumors induced in mice by a wide range of physical (high- and low-energy radiation) and chemical carcinogens to which humans are exposed. In collaboration with the National Toxicology Program and the Sanger Institute (UK), we have carried out whole-genome and/or -exome sequencing of several hundred mouse tumors induced by a wide range of known or suspected human carcinogens. Our data identify highly variable tumor genomic imprints of carcinogen exposure as reflected in the relative numbers and types of structural variants (copy number changes, translocations, complex rearrangements) and point mutational signatures found in tumors induced by different agents. Analysis of these mutation patterns may illuminate the specific mechanisms by which these agents act to initiate or promote cancer development and provide novel information for use in risk assessment.
Citation Format: Allan Balmain. Mutational signatures of environmental carcinogens in mouse and human cancers [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr IA06.
Abstract PR07: Latent class analysis of multipollutant exposure
Authors: Larsen Alexandra , Kolpacoff Viktoria , McCormack Kara , Hyslop Terry 
Published: June 2022

Abstract
Recent work suggests that air pollutants, toxic chemicals, and other environmental exposures negatively impact health in a synergistic way. In order to measure and understand this impact, we propose a latent class mixture model of multipollutant exposure. Our model incorporates the joint behavior of individual pollutants that inform overall exposure levels and provides clear measures of multipollutant exposure. We identify low, medium, and high levels of joint exposure to volatile organic compounds (VOC), particulate matter (PM), and heavy metals (HM), and present estimated class-membership for each census tract in the US (&gt;76,000). We use publicly available data from the EPA, including the National Air Toxics Assessment (NATA), measured at the census tract level. Model results indicate that mixtures of 5 levels of VOC, 2 levels of PM, and 4 levels of HM best fit data at the national level. Twelve percent of U.S. census tracts are in the highest levels of all 3 categories of pollutants. While frequently observed in metropolitan areas, rural areas are sometimes detected at the highest levels, as well. Our next focus is to incorporate spatial correlations as well as linkages to our earlier latent model work on socioeconomic status (SES). Taken together, these extensions can then be incorporated into a holistic, exposome modeling framework for estimating disparities in cancer survival.
This abstract is also being presented as Poster A31.
Citation Format: Alexandra Larsen, Viktoria Kolpacoff, Kara McCormack, Terry Hyslop. Latent class analysis of multipollutant exposure [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr PR07.
Twenty-Four-Hour Pulsatile Hemodynamics Predict Brachial Blood Pressure Response to Renal Denervation in the SPYRAL HTN-OFF MED Trial
Authors: Weber Thomas , Wassertheurer Siegfried , Mayer Christopher C. , Hametner Bernhard , Danninger Kathrin , Townsend Raymond R. , Mahfoud Felix , Kario Kazuomi , Fahy Martin , DeBruin Vanessa , Peterson Nicole , Negoita Manuela , Weber Michael A. , Kandzari David E. , Schmieder Roland E. , Tsioufis Konstantinos P. , Binder Ronald K. , Böhm Michael 
Published: June 2022

Background:
Renal denervation (RDN) lowers blood pressure (BP), but BP response is variable in individual patients. We investigated whether measures of pulsatile hemodynamics, obtained during 24-hour ambulatory BP monitoring, predict BP drop following RDN.

Methods:
From the randomized, sham-controlled SPYRAL HTN-OFF MED Pivotal trial, we performed a post hoc analysis of BP waveforms from 111 RDN patients and 111 sham controls, obtained with a brachial cuff-based sphygmomanometer. Waveforms were acquired during ambulatory BP monitoring at diastolic BP level and processed with validated ARCSolver algorithms to derive hemodynamic parameters (augmentation index; augmentation pressure; backward and forward wave amplitude; estimated aortic pulse wave velocity). We investigated the relationship between averaged 24-hour values at baseline and the change in 24-hour BP at 3 months in RDN patients, corrected for observed trends in the sham group.

Results:

There was a consistent inverse relationship between baseline augmentation index/augmentation pressure/backward wave amplitude/forward wave amplitude/estimated aortic pulse wave velocity and BP response to RDN: the decrease in 24-hour systolic BP/diastolic BP was 7.8/5.9 (augmentation index), 8.0/6.3 (augmentation pressure), 6.7/5.4 (backward wave amplitude), 5.7/4.7 (forward wave amplitude), and 7.8/5.2 (estimated aortic pulse wave velocity) mm Hg greater for patients below versus above the respective median value (
P
<0.001 for all comparisons, respectively). Taking augmentation index/augmentation pressure/backward wave amplitude/forward wave amplitude/estimated aortic pulse wave velocity into account, a favorable BP response following RDN, defined as a drop in 24-hour systolic blood pressure of ≥5 mm Hg, could be predicted with an area under the curve of 0.70/0.74/0.70/0.65/0.62 (
P
<0.001 for all, respectively).

Conclusions:
These results suggest that pulsatile hemodynamics, obtained during 24-hour ambulatory BP monitoring, may predict BP response to RDN.
Effect of Renin-Angiotensin-Aldosterone System Inhibitors on the Rupture Risk Among Hypertensive Patients With Intracranial Aneurysms
Authors: Zhong Ping , Lu Zhiwen , Li Zhangyu , Li Tianxiao , Lan Qing , Liu Jianmin , Wang Zhanxiang , Chen Sifang , Huang Qinghai 
Published: June 2022

Background:
Mounting experimental evidence supports the concept that the RAAS (renin-angiotensin-aldosterone system) is involved in the pathogenesis of intracranial aneurysm rupture. However, whether RAAS inhibitors could reduce the rupture risk of intracranial aneurysms remains unclear.

Methods:
We performed a chart review of a multicenter, prospectively maintained database of 3044 hypertensive patients with intracranial aneurysms from 20 medical centers in China. The patients were separated into ruptured and unruptured groups. Univariable and multivariable logistical regression analyses were performed to determine the association between the use of RAAS inhibitors and the rupture risk. Sensitivity analyses and subgroup analyses were performed to verify the robustness of the results.

Results:

In multivariable analyses, female sex, passive smoking, uncontrolled, or unmonitored hypertension, use of over 2 antihypertensive medications, RAAS inhibitors use, antihyperglycemic agents use, hyperlipidemia, ischemic stroke, and aneurysmal location were independently associated with the rupture risk. The use of RAAS inhibitors was significantly associated with a reduced rupture risk compared with the use of non-RAAS inhibitors (odds ratio, 0.490 [95% CI, 0.402–0.597];
P
=0.000). Compared with the use of non-RAAS inhibitors, the use of ACE (angiotensin-converting enzyme) inhibitors (odds ratio, 0.559 [95% CI, 0.442–0.709];
P
=0.000) and use of ARBs (angiotensin receptor blockers; odds ratio, 0.414 [95% CI, 0.315–0.542];
P
=0.000) were both significantly associated with a reduced rupture risk. The negative association of the rupture risk with RAAS inhibitors was consistent across 3 analyzed data and the predefined subgroups (including controlled hypertension).

Conclusions:
The use of RAAS inhibitors was significantly associated with a decreased rupture risk independent of blood pressure control among hypertensive patients with intracranial aneurysms.
Mineralocorticoid Receptor Antagonists Cause Natriuresis in the Absence of Aldosterone
Authors: Maeoka Yujiro , Su Xiao-Tong , Wang Wen-Hui , Duan Xin-Peng , Sharma Avika , Li Na , Staub Olivier , McCormick James A. , Ellison David H. 
Published: June 2022

Background:
MR (mineralocorticoid receptor) antagonists are recommended for patients with resistant hypertension even when circulating aldosterone levels are not high. Although aldosterone activates MR to increase epithelial sodium channel (ENaC) activity, glucocorticoids also activate MR but are metabolized by 11βHSD2 (11β-hydroxysteroid dehydrogenase type 2). 11βHSD2 is expressed at increasing levels from distal convoluted tubule (DCT) through collecting duct. Here, we hypothesized that MR maintains ENaC activity in the DCT2 and early connecting tubule in the absence of aldosterone.

Methods:

We studied AS (aldosterone synthase)-deficient (AS
−/−
) mice, which were backcrossed onto the same C57BL6/J strain as kidney-specific MR knockout (KS-MR
−/−
) mice. KS-MR
−/−
mice were used to compare MR expression and ENaC localization and cleavage with AS
−/−
mice.

Results:

MR was highly expressed along DCT2 through the cortical collecting duct (CCD), whereas no 11βHSD2 expression was observed along DCT2. MR signal and apical ENaC localization were clearly reduced along both DCT2 and CCD in KS-MR
−/−
mice but were fully preserved along DCT2 and were partially reduced along CCD in AS
−/−
mice. Apical ENaC localization and ENaC currents were fully preserved along DCT2 in AS
−/−
mice and were not increased along CCD after low salt. AS
−/−
mice exhibited transient Na
+
wasting under low-salt diet, but administration of the MR antagonist eplerenone to AS
−/−
mice led to hyperkalemia and decreased body weight with higher Na
+
excretion, mimicking the phenotype of MR
−/−
mice.

Conclusions:

Our results provide evidence that MR is activated in the absence of aldosterone along DCT2 and partially CCD, suggesting glucocorticoid binding to MR preserves sodium homeostasis along DCT2 in AS
−/−
mice.
Differences in Regulation of Cortisol Secretion Contribute to Left Ventricular Abnormalities in Patients With Essential Hypertension
Authors: Brosolo Gabriele , Catena Cristiana , Da Porto Andrea , Bulfone Luca , Vacca Antonio , Verheyen Nicolas D. , Sechi Leonardo A. 
Published: June 2022

Background:
Left ventricular (LV) abnormalities were reported in patients with overt and subclinical Cushing syndrome. The aim of this study was to investigate the relationships of daily plasma cortisol profile and cortisol response to an overnight suppression test with cardiac changes in patients with hypertension.

Methods:

In a cross-sectional study, we included 136 nondiabetic, patients with essential hypertension who were free of cardiovascular and renal complications. Plasma cortisol was measured at 8
am
, 3
pm
, and 12
am
and at 8
am
after overnight suppression with 1 mg dexamethasone (dexamethasone suppression test [DST]). Echocardiography was performed with standard B-mode and tissue-Doppler imaging.

Results:

LV hypertrophy was present in 30% and LV diastolic dysfunction in 51% of patients who were older and had significantly higher body mass index, systolic blood pressure, duration of hypertension, and 12
am
and DST cortisol. LV mass index and relative wall thickness increased progressively across tertiles of DST cortisol, together with progressive worsening of diastolic function. LV mass index was directly related to age, systolic blood pressure, duration of hypertension, and 12
am
and DST cortisol, and inversely to creatinine clearance. Multivariate regression analysis showed independent correlation of LV mass index with body mass index, systolic blood pressure, and 12
am
and DST cortisol. Logistic regression showed that DST cortisol independently predicted LV hypertrophy.

Conclusions:
Midnight and DST plasma cortisol levels are independent determinants of LV mass and geometry in patients with essential hypertension suggesting that even minor changes in regulation of cortisol secretion could contribute to cardiac abnormalities in these patients.