bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fault failure modes, deformation mechanisms, dilation tendency, slip tendency, and conduits v. seals
Authors: Ferrill David A. , Smart Kevin J. , Morris Alan P. 
Published: November 2019

Abstract
Faults have complicated shapes. Non-planarity of faults can be caused by variations in failure modes, which in turn are dictated by mechanical stratigraphy interacting with the ambient stress field, as well as by linkage of fault segments. Different portions of a fault or fault zone may experience volume gain, volume conservation and volume loss simultaneously depending on the position along a fault's surface, the stresses resolved on the fault and the associated deformation mechanisms. This variation in deformation style and associated volume change has a profound effect on the ability of a fault to transmit (or impede) fluid both along and across the fault. In this paper we explore interrelated concepts of failure mode and resolved stress analysis, and provide examples of fault geometry in normal faulting and reverse faulting stress regimes that illustrate the effects of fault geometry on failure behaviour and related importance to fluid transmission. In particular, we emphasize the utility of using relative dilation tendency v. slip tendency on fault patches as a predictor of deformation behaviour, and suggest this parameter space as a new tool for evaluating conduit v. seal behaviour of faults.
The 11th workshop on active internet measurements (AIMS-11) workshop report
Authors: Claffy K C , Clark David 
Published: November 2019

On 16-17 April 2018, CAIDA hosted its eleventh Workshop on Active Internet Measurements (AIMS-11). This workshop series provides a forum for stakeholders in Internet active measurement projects to communicate their interests and concerns, and explore cooperative approaches to maximizing the collective benefit of deployed infrastructure and gathered data. An overarching theme this year was scaling the storage, indexing, annotation, and usage of Internet measurements. We discussed tradeoffs in use of commercial cloud services to to make measurement results more accessible and informative to researchers in various disciplines. Other agenda topics included status updates on recent measurement infrastructures and community feedback; measurement of poorly configured infrastructure; and recent successes and approaches to evolving challenges in geolocation, topology, route hijacking, and performance measurement. We review highlights of discussions of the talks. This report does not cover each topic discussed; for more details examine workshop presentations linked from the workshop web page:
http://www.caida.org/workshops/aims/1904/.
EZH2 Loss Drives Resistance to Carboplatin and Paclitaxel in Serous Ovarian Cancers Expressing ATM
Authors: Naskou Johanna , Beiter Yvonne , van Rensburg Ruan , Honisch Ellen , Rudelius Martina , Schlensog Martin , Gottstein Julia , Walter Larissa , Braicu Elena I. , Sehouli Jalid , Darb-Esfahani Silvia , Staebler Annette , Hartkopf Andreas D. , Brucker Sara , Wallwiener Diethelm , Beyer Ines , Niederacher Dieter , Fehm Tanja , Templin Markus F. , Neubauer Hans 
Published: November 2019

Abstract

Mechanisms of intrinsic resistance of serous ovarian cancers to standard treatment with carboplatin and paclitaxel are poorly understood. Seventeen primary serous ovarian cancers classified as responders or nonresponders to standard treatment were screened with DigiWest protein array analysis for 279 analytes. Histone methyl transferase EZH2, an interaction partner of ataxia telangiectasia mutated (ATM), was found as one of the most significantly represented proteins in responsive tumors. Survival analysis of 616 patients confirmed a better outcome in patients with high EZH2 expression, but a worse outcome in patients with low EZH2 and high-ATM–expressing tumors compared with patients with low EZH2 and low-ATM–expressing tumors. A proximity ligation assay further confirmed an association between ATM and EZH2 in tumors of patients with an increased disease-free survival. Knockdown of EZH2 resulted in treatment-resistant cells, but suppression of both EZH2 and ATM, or ATM alone, had no effect. DigiWest protein analysis of EZH2-knockdown cells revealed a decrease in proteins involved in mitotic processes and checkpoint regulation, suggesting that deregulated ATM may induce treatment resistance.

Implications:
Ovarian cancer is a malignancy with high mortality rates, with to date, no successful molecular characterization strategies. Our study uncovers in a comprehensive approach the involvement of checkpoint regulation via ATM and EZH2, potentially providing a new therapeutic perspective for further investigations.
Genomic Characteristics of Triple-Negative Breast Cancer Nominate Molecular Subtypes That Predict Chemotherapy Response
Authors: Kim Jihyun , Yu Doyeong , Kwon Youngmee , Lee Keun Seok , Sim Sung Hoon , Kong Sun-Young , Lee Eun Sook , Park In Hae , Park Charny 
Published: November 2019

AbstractThe heterogeneity of triple-negative breast cancer (TNBC) poses difficulties for suitable treatment and leads to poor outcome. This study aimed to define a consensus molecular subtype (CMS) of TNBC and thus elucidate genomic characteristics and relevant therapy. We integrated the expression profiles of 957 TNBC samples from published datasets. We identified genomic characteristics of subtype by exploring the pathway activity, microenvironment, and clinical relevance. In addition, drug response (DR) scores (n = 181) were computationally investigated using chemical perturbation gene signatures and validated in our own patient with TNBC (n = 38) who received chemotherapy and organoid biobank data (n = 64). Subsequently, cooperative functions with drugs were also explored. Finally, we classified TNBC into four CMSs: stem-like; mesenchymal-like; immunomodulatory; luminal-androgen receptor. CMSs also elucidated distinct tumor-associated microenvironment and pathway activities. Furthermore, we discovered metastasis-promoting genes, such as secreted phosphoprotein 1 by comparing with primary. Computational DR scores associated with CMS revealed drug candidates (n = 18), and it was successfully evaluated in cisplatin response of both patients and organoids. Our CMS recapitulated in-depth functional and cellular heterogeneity encompassing primary and metastatic TNBC. We suggest DR scores to predict CMS-specific DRs and to be successfully validated. Finally, our approach systemically proposes a relevant therapeutic prediction model as well as prognostic markers for TNBC.Implications:We delineated the genomic characteristic and computational DR prediction for TNBC CMS from gene expression profile. Our systematic approach provides diagnostic markers for subtype and metastasis verified by machine-learning and novel therapeutic candidates for patients with TNBC.
Lysine-Specific Demethylase 1 Mediates AKT Activity and Promotes Epithelial-to-Mesenchymal Transition in PIK3CA-Mutant Colorectal Cancer
Authors: Miller Samuel A. , Policastro Robert A. , Savant Sudha S. , Sriramkumar Shruthi , Ding Ning , Lu Xiaoyu , Mohammad Helai P. , Cao Sha , Kalin Jay H. , Cole Philip A. , Zentner Gabriel E. , O'Hagan Heather M. 
Published: November 2019

Abstract

Activation of the epithelial-to-mesenchymal transition (EMT) program is a critical mechanism for initiating cancer progression and migration. Colorectal cancers contain many genetic and epigenetic alterations that can contribute to EMT. Mutations activating the PI3K/AKT signaling pathway are observed in &gt;40% of patients with colorectal cancer contributing to increased invasion and metastasis. Little is known about how oncogenic signaling pathways such as PI3K/AKT synergize with chromatin modifiers to activate the EMT program. Lysine-specific demethylase 1 (LSD1) is a chromatin-modifying enzyme that is overexpressed in colorectal cancer and enhances cell migration. In this study, we determine that LSD1 expression is significantly elevated in patients with colorectal cancer with mutation of the catalytic subunit of PI3K, PIK3CA, compared with patients with colorectal cancer with WT PIK3CA. LSD1 enhances activation of the AKT kinase in colorectal cancer cells through a noncatalytic mechanism, acting as a scaffolding protein for the transcription-repressing CoREST complex. In addition, growth of PIK3CA-mutant colorectal cancer cells is uniquely dependent on LSD1. Knockdown or CRISPR knockout of LSD1 blocks AKT-mediated stabilization of the EMT-promoting transcription factor Snail and effectively blocks AKT-mediated EMT and migration. Overall, we uniquely demonstrate that LSD1 mediates AKT activation in response to growth factors and oxidative stress, and LSD1-regulated AKT activity promotes EMT-like characteristics in a subset of PIK3CA-mutant cells.

Implications:
Our data support the hypothesis that inhibitors targeting the CoREST complex may be clinically effective in patients with colorectal cancer harboring PIK3CA mutations.
Bisphosphonates Zometa and Fosamax Synergize with Metformin to Prevent AOM-Induced Colon Cancer in F344 Rat Model
Authors: Madka Venkateshwar , Kumar Gaurav , Pathuri Gopal , Zhang Yuting , Lightfoot Stanley , Asch Adam S. , Mohammed Altaf , Steele Vernon E. , Rao Chinthalapally V. 
Published: November 2019

Abstract
Recent observational studies suggest that bisphosphonates (BP) and antidiabetic drugs are associated with colorectal cancer risk reduction. Hence, we evaluated the colorectal cancer preventive effects of BPs (zometa and fosamax), individually and when combined with metformin, in azoxymethane-induced rat colon cancer model. Rat (30/group) were randomized and treated subcutaneously with azoxymethane to induce colorectal cancer. Dietary intervention with zometa or fosamax (0, 20, or 100 ppm) or metformin (1,000 ppm) or the combinations (zometa/fosamax 20 ppm plus metformin 1,000 ppm) began 4 weeks after azoxymethane treatment, at premalignant lesions stage. Rats were killed 40 weeks post drug intervention to assess colorectal cancer preventive efficacy. Dietary zometa (20 ppm) inhibited noninvasive adenocarcinomas multiplicity by 37% (P &lt; 0.03) when compared with control diet fed group. Fosamax at 20 ppm and 100 ppm significantly reduced adenocarcinoma incidence (P &lt; 0.005) and inhibited the noninvasive adenocarcinoma multiplicities by 43.8% (P &lt; 0.009) and 60.8% (P &lt; 0.004), respectively, compared with the group fed control diet. At 1,000 ppm dose, metformin failed to suppress colon adenocarcinoma formation. However, the lower dose combinations of zometa or fosamax with metformin resulted in significant inhibition of noninvasive adenocarcinoma by 48% (P &lt; 0.006) and 64% (P &lt; 0.0002), and invasive adenocarcinoma by 49% (P &lt; 0.0005) and 38% (P &lt; 0.006), respectively. Biomarker analysis of combination drug–treated tumors showed a decrease in cell proliferation with increased apoptosis when compared with untreated tumors. Overall, our results suggest that the combination of low doses of zometa or fosamax with metformin showed synergistic effect and significantly inhibited colon adenocarcinoma incidence and multiplicity.
Use of Diffusion‐Weighted Imaging‐Alberta Stroke Program Early Computed Tomography Score (DWI‐ASPECTS) and Ischemic Core Volume to Determine the Malignant Profile in Acute Stroke
Authors: Yoshimoto Takeshi , Inoue Manabu , Yamagami Hiroshi , Fujita Kyohei , Tanaka Kanta , Ando Daisuke , Sonoda Kazutaka , Kamogawa Naruhiko , Koga Masatoshi , Ihara Masafumi , Toyoda Kazunori 
Published: November 2019

Background
Malignant profiles were identified by imaging profiles and unfavorable outcomes that have poor response to reperfusion therapy. Many trials have used this profile in their inclusion criteria including large‐vessel occlusion acute ischemic stroke trials. We aimed to redefine the cutoff values for malignant profile in acute ischemic stroke patients with large‐vessel occlusion regardless of reperfusion therapy.

Methods and Results

Consecutive acute ischemic stroke patients with anterior large‐vessel occlusion were prospectively extracted from the National Cerebral and Cardiovascular Center Stroke Registry between March 2014 and December 2017. Diffusion‐Weighted Imaging‐Alberta Stroke Program Early Computed Tomography Score (DWI‐ASPECTS) and diffusion‐weighted imaging lesion ischemic core volume (Vol

DWI

) were measured in acute ischemic stroke patients with large‐vessel occlusion with or without treatment. Unfavorable outcome was defined as a modified Rankin Scale score 5 to 6 at 3 months, and optimal
DWI
‐
ASPECTS
and Vol

DWI

for unfavorable outcome were assessed. In total, 198 patients (111 men, 77±13 years old) were enrolled. Median
DWI
‐
ASPECTS
was 7 (5‐9), and median Vol

DWI

was 55 (6‐134)
mL
. Among the patients, 72 (36%) patients underwent reperfusion therapy, and 83 (42%) had unfavorable outcomes. The threshold values for a malignant profile on receiver operating characteristic curve analysis for
DWI
‐
ASPECTS
and Vol

DWI

were 4 (area under the curve 0.78,
P
<0.01; sensitivity 0.71, specificity 0.75) and 71 mL (area under the curve 0.80,
P
<0.01; sensitivity 0.76, specificity 0.77), respectively.

Conclusions

The cutoff values for our redefined malignant profile were
DWI
‐
ASPECTS
4 and Vol

DWI

71 mL with no selection bias for reperfusion therapy in the real‐world clinical practice.

Clinical Trial Registration

URL
:
http://www.clinicaltrials.gov
Unique identifier:
NCT
02251665
Risk of Major Adverse Cardiovascular Events and Major Hemorrhage Among White and Black Patients Undergoing Percutaneous Coronary Intervention
Authors: Cai Anping , Dillon Chrisly , Hillegass William B. , Beasley Mark , Brott Brigitta C. , Bittner Vera A. , Perry Gilbert J. , Halade Ganesh V. , Prabhu Sumanth D. , Limdi Nita A. 
Published: November 2019

Background

Data on racial disparities in major adverse cardiovascular events (
MACE
) and major hemorrhage (
HEM
) after percutaneous coronary intervention are limited. Factors contributing to these disparities are unknown.

Methods and Results

PR
i
ME
‐GGAT (Pharmacogenomic Resource to Improve Medication Effectiveness–Genotype‐Guided Antiplatelet Therapy) is a prospective cohort. Patients aged ≥18 years undergoing percutaneous coronary intervention were enrolled and followed for up to 1 year. Racial disparities in risk of
MACE
and
HEM
were assessed using an incident rate ratio. Sequential cumulative adjustment analyses were performed to identify factors contributing to these disparities. Data from 919 patients were included in the analysis. Compared with white patients, black patients (n=203; 22.1% of the cohort) were younger and were more likely to be female, to be a smoker, and to have higher body mass index, lower socioeconomic status, higher prevalence of diabetes mellitus and moderate to severe chronic kidney disease, and presentation with acute coronary syndrome and to undergo urgent percutaneous coronary intervention. The incident rates of
MACE
(34.1% versus 18.2% per 100 person‐years,
P
<0.001) and
HEM
(17.7% versus 10.3% per 100 person‐years,
P
=0.02) were higher in black patients. The incident rate ratio was 1.9 (95% CI, 1.3–2.6;
P
<0.001) for
MACE
and 1.7 (95%
CI
, 1.1–2. 7;
P
=0.02) for
HEM
. After adjustment for nonclinical and clinical factors, black race was not significantly associated with outcomes. Rather, differences in socioeconomic status, comorbidities, and coronary heart disease severity were attributed to racial disparities in outcomes.

Conclusions

Despite receiving similar treatment, racial disparities in
MACE
and
HEM
still exist. Opportunities exist to narrow these disparities by mitigating the identified contributors.
Predictors and Clinical Outcomes of Vasoplegia in Patients Bridged to Heart Transplantation With Continuous‐Flow Left Ventricular Assist Devices
Authors: Asleh Rabea , Alnsasra Hilmi , Daly Richard C. , Schettle Sarah D. , Briasoulis Alexandros , Taher Riad , Dunlay Shannon M. , Stulak John M. , Behfar Atta , Pereira Naveen L. , Frantz Robert P. , Edwards Brooks S. , Clavell Alfredo L. , Kushwaha Sudhir S. 
Published: November 2019

Background

The presence of a durable left ventricular assist device (
LVAD
) is associated with increased risk of vasoplegia in the early postoperative period following heart transplantation (
HT
). However, preoperative predictors of vasoplegia and its impact on survival after
HT
are unknown. We sought to examine predictors and outcomes of patients who develop vasoplegia after
HT
following bridging therapy with an
LVAD
.

Methods and Results

We identified 94 patients who underwent
HT
after bridging with continuous‐flow
LVAD
from 2008 to 2018 at a single institution. Vasoplegia was defined as persistent low vascular resistance requiring ≥2 intravenous vasopressors within 48 hours after
HT
for >24 hours to maintain mean arterial pressure >70 mm Hg. Overall, 44 patients (46.8%) developed vasoplegia after
HT
. Patients with and without vasoplegia had similar preoperative
LVAD
, echocardiographic, and hemodynamic parameters. Patients with vasoplegia were significantly older; had longer
LVAD
support, higher preoperative creatinine, longer cardiopulmonary bypass time, and higher Charlson comorbidity index; and more often underwent combined organ transplantation. In a multivariate logistic regression model, older age (odds ratio: 1.08 per year;
P
=0.010), longer
LVAD
support (odds ratio: 1.06 per month;
P
=0.007), higher creatinine (odds ratio: 3.9 per 1 mg/dL;
P
=0.039), and longer cardiopulmonary bypass time (odds ratio: 1.83 per hour;
P
=0.044) were independent predictors of vasoplegia. After mean follow‐up of 4.0 years after
HT
, vasoplegia was associated with increased risk of all‐cause mortality (hazard ratio: 5.20; 95% CI, 1.71–19.28;
P
=0.003).

Conclusions

Older age, longer
LVAD
support, impaired renal function, and prolonged intraoperative
CPB
time are independent predictors of vasoplegia in patients undergoing
HT
after
LVAD
bridging. Vasoplegia is associated with worse prognosis; therefore, detailed assessment of these predictors can be clinically important.
Left Ventricular Unloading Increases the Coronary Collateral Flow Index Before Reperfusion and Reduces Infarct Size in a Swine Model of Acute Myocardial Infarction
Authors: Briceno Natalia , Annamalai Shiva K. , Reyelt Lara , Crowley Paige , Qiao Xiaoying , Swain Lija , Pedicini Robert , Foroutanjazi Sina , Jorde Lena , Yesodharan Gemini , Perera Divaka , Kapur Navin K. 
Published: November 2019

Background

Unloading the left ventricle and delaying reperfusion reduces infarct size in preclinical models of acute myocardial infarction. We hypothesized that a potential explanation for this effect is that left ventricular (
LV
) unloading before reperfusion increases collateral blood flow to ischemic myocardium.

Methods and Results

Acute myocardial infarction was induced by balloon occlusion of the left anterior descending artery for 120 minutes in adult swine, followed by reperfusion for 180 minutes. After 90 minutes of occlusion, animals were assigned to 30 minutes of continued occlusion (n=6) or to 30 minutes of support with either an Impella
CP
(n=4) or venoarterial extracorporeal membrane oxygenation (n=5) with persistent occlusion. The primary end point was measures of microcirculatory blood flow including the collateral flow index (
CFI
) during left anterior descending artery occlusion as (P
w
−
RA
)/(P
a
−
RA
), where P
a
, P
w
, and
RA
are aortic, coronary wedge, and right atrial pressure, respectively. Infarct size was quantified using triphenyltetrazolium chloride. Compared with continued occlusion, Impella, not venoarterial extracorporeal membrane oxygenation, reduced infarct size relative to the area at risk. Before reperfusion, Impella reduced
LV
stroke work by 25% and increased the
CFI
by 75%, but venoarterial extracorporeal membrane oxygenation did not. Among all groups, the change in
CFI
between 90 and 120 minutes correlated inversely with the change in LV stroke work (
r
2
=0.44,
P
=0.01) and infarct size (
r
2
=0.41,
P
=0.02).

Conclusions

We report for the first time that 30 minutes of
LV
unloading during coronary occlusion increases the
CFI
, which correlates inversely with
LV stroke work
and infarct size. Venoarterial extracorporeal membrane oxygenation failed to increase the
CFI
and did not reduce infarct size.
Prognostic Impact of Baseline Hemoglobin Levels on Long‐Term Thrombotic and Bleeding Events After Percutaneous Coronary Interventions
Authors: Nagao Kazuya , Watanabe Hirotoshi , Morimoto Takeshi , Inada Tsukasa , Hayashi Fujio , Nakagawa Yoshihisa , Furukawa Yutaka , Kadota Kazushige , Akasaka Takashi , Natsuaki Masahiro , Kozuma Ken , Tanabe Kengo , Morino Yoshihiro , Shiomi Hiroki , Kimura Takeshi ,   the CREDO‐Kyoto PCI/CABG Registry Cohort‐2, RESET, and NEXT Investigators
Published: November 2019

Background
Association of baseline hemoglobin levels with long‐term adverse events after percutaneous coronary interventions has not been yet thoroughly defined. We aimed to assess the clinical impact of baseline hemoglobin on long‐term ischemic and bleeding risk after percutaneous coronary intervention.

Methods and Results

Using the pooled individual patient‐level data from the 3 percutaneous coronary intervention studies, we categorized 19 288 patients into 4 groups: high‐normal hemoglobin (≥14.0 g/dL; n=7555), low‐normal hemoglobin (13.0–13.9 g/dL in men and 12.0–13.9 g/dL in women; n=5303), mild anemia (11.0–12.9 g/dL in men and 11.0–11.9 g/dL in women; n=4117), and moderate/severe anemia (<11.0 g/dL; n=2313). Median follow‐up duration was 3 years. Low‐normal hemoglobin, mild anemia, and moderate/severe anemia correlated with significant excess risk relative to high‐normal hemoglobin for
GUSTO
(Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries Trial) moderate/severe bleeding, with adjusted hazard ratios of 1.22 (95% CI, 1.04–1.44), 1.73 (95% CI, 1.47–2.04), and 2.31 (95% CI, 1.92–2.78), respectively. Moderate/severe anemia also correlated with significant excess risk relative to high‐normal hemoglobin for the ischemic composite end point of myocardial infarction/ischemic stroke (adjusted hazard ratio, 1.33; 95% CI, 1.11–1.60), whereas low‐normal hemoglobin and mild anemia did not. However, the excess risk of low‐normal hemoglobin, mild anemia, and moderate/severe anemia relative to high‐normal hemoglobin remained significant for ischemic stroke and for mortality.

Conclusions
Decreasing baseline hemoglobin correlated with incrementally higher long‐term risk for major bleeding, ischemic stroke, and mortality after percutaneous coronary intervention. Even within normal range, lower baseline hemoglobin level correlated with higher ischemic and bleeding risk.