bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenetic and Oncogenic Inhibitors Cooperatively Drive Differentiation and Kill KRAS-Mutant Colorectal Cancers
Authors: Loi Patrick , Schade Amy E. , Rodriguez Carrie L. , Krishnan Anjana , Perurena Naiara , Nguyen Van T.M. , Xu Yilin , Watanabe Marina , Davis Rachel A. , Gardner Alycia , Pilla Natalie F. , Mattioli Kaia , Popow Olesja , Gunduz Nuray , Lannagan Tamsin R.M. , Fitzgerald Samantha , Sicinska Ewa T. , Lin Jia-Ren , Tan William , Brais Lauren K. , Haigis Kevin M. , Giannakis Marios , Ng Kimmie , Santagata Sandro , Helin Kristian , Sansom Owen J. , Cichowski Karen 
Published: August 2024

Abstract
Current treatments for KRAS-mutant colorectal cancers are often limited by cellular plasticity and rewiring responses. Here we describe a promising therapeutic strategy that simultaneously targets epigenetic and oncogenic signals. Specifically, we show that inhibitors of histone methyltransferase, EZH2, synergize with various rat sarcoma virus (RAS) pathway inhibitors and promote dramatic tumor regression in vivo. Together these agents cooperatively suppress Wingless and Int-1 (WNT)-driven transcription and drive colorectal cancers into a more differentiated cell state by inducing the Groucho/transducin-like enhancer corepressor, TLE4, along with a network of WNT pathway inhibitors and intestinal differentiation proteins. However, these agents also induce the proapoptotic protein BCL2 modifying factor (BMF), which subsequently kills these more differentiated cells. Accordingly, cell death can be prevented by activating β-catenin, by blocking differentiation, or by ablating BMF expression. Collectively, these studies reveal a new therapeutic approach for treating KRAS-mutant colorectal cancers and illustrate a critical convergence of EZH2 and RAS on oncogenic WNT signals, intestinal differentiation, and apoptosis.

Significance:
Combined EZH2 and RAS pathway inhibitors kill KRAS-mutant colorectal cancer cells and promote durable tumor regression in vivo. These agents function by cooperatively suppressing the WNT pathway, driving differentiation, and epigenetically reprogramming cells to permit the induction of apoptotic signals, which then kill these more differentiated tumor cells.
Acute Sympathetic Blockade Improves Insulin‐Mediated Microvascular Blood Flow in the Forearm of Adult Human Subjects With Obesity
Authors: Smith Emily C. , Patel Jay N. , Wahba Amr , Cluckey Andrew , Celedonio Jorge , Park JinWoo , Hannah LaToya , Lonce Suzanna , Shibao Cyndya A. , Paranjape Sachin Y. , Diedrich Andre , McGuinness Owen , Wasserman David H. , Biaggioni Italo , Gamboa Alfredo 
Published: August 2024

Background
Obesity is associated with resistance to the metabolic (glucose uptake) and vascular (nitric‐oxide mediated dilation and microvascular recruitment) actions of insulin. These vascular effects contribute to insulin sensitivity by increasing tissue delivery of glucose. Studies by us and others suggest that sympathetic activation contributes to insulin resistance to glucose uptake. Here we tested the hypothesis that sympathetic activation contributes to impaired insulin‐mediated vasodilation in adult subjects with obesity.

Methods and Results

In a randomized crossover study, we used a euglycemic hyperinsulinemic clamp in 12 subjects with obesity to induce forearm arterial vasodilation (forearm blood flow) and microvascular recruitment (contrast‐enhanced ultrasonography) during an intrabrachial infusion of saline (control) or phentolamine (sympathetic blockade). Insulin increased forearm blood flow on both study days (from 2.21±1.22 to 4.89±4.21 mL/100 mL per min,
P
=0.003 and from 2.42±0.89 to 7.19±3.35 mL/100 mL per min,
P
=0.002 for the intact and blocked day, respectively). Sympathetic blockade with phentolamine resulted in a significantly greater increase in microvascular flow velocity (∆microvascular flow velocity: 0.23±0.65 versus 2.51±3.01 arbitrary intensity units (AIU/s) for saline and phentolamine respectively,
P
=0.005), microvascular blood volume (∆microvascular blood volume: 1.69±2.45 versus 3.76±2.93 AIU, respectively,
P
=0.05), and microvascular blood flow (∆microvascular blood flow: 0.28±0.653 versus 2.51±3.01 AIU
2
/s, respectively,
P
=0.0161). To evaluate if this effect was not due to nonspecific vasodilation, we replicated the study in 6 subjects with obesity comparing intrabrachial infusion of phentolamine to sodium nitroprusside. At doses that produced similar increases in forearm blood flow, insulin‐induced changes in microvascular flow velocity were greater during phentolamine than sodium nitroprusside (%microvascular flow velocity=58% versus 29%, respectively,
P
=0.031).

Conclusions
We conclude that sympathetic activation impairs insulin‐mediated microvascular recruitment in adult subjects with obesity.
Safety of Antiplatelet Therapy in Noncardioembolic Ischemic Stroke With Thrombocytopenia: The CASE II Study
Authors: Xu Dongjuan , Zhou Huan , Zhang Tingxia , Gong Weiwei , Zhong Jieming , Yu Han , Chen Fujian , Zhong Wansi , Yan Shenqiang , Lou Min ,   the CASE II investigators
Published: August 2024

Background
There is scant evidence regarding the safety of antiplatelet therapy in acute ischemic stroke (AIS) patients with thrombocytopenia. Our study aims to address this concern by examining AIS patients with thrombocytopenia from a large database in real‐world settings.

Methods and Results

We included patients with AIS with a platelet count <100×10
9
/L who had complete records of antiplatelet drug use. Those requiring anticoagulation or having contraindications to antiplatelet therapy were excluded. Short‐term safety outcomes were in‐hospital bleeding events, while the long‐term safety outcome was 1‐year all‐cause mortality. A good clinical outcome was defined as functional independence, indicated by a modified Rankin Scale score of 0 to 2 at discharge. Propensity score matched analyses were used. We screened 169 423 patients with AIS from 90 stroke centers in the CASE II register, ultimately enrolling 2808 noncardioembolic patients with thrombocytopenia. In the propensity score matched analyses, no significant difference was observed between the antiplatelet and nonantiplatelet groups in terms of intracranial hemorrhage (odds ratio=0.855 [95% CI, 0.284–5.478];
P
=0.160) or gastrointestinal bleeding (odds ratio=2.034 [95% CI, 0.755–5.478];
P
=0.160). Antiplatelet therapy was associated with improved functional outcomes at discharge (odds ratio=1.405 [95% CI, 1.028–1.920];
P
=0.033), and showed a trend towards reducing 1‐year mortality (odds ratio=0.395 [95% CI, 0.152–1.031];
P
=0.058).

Conclusions
The use of antiplatelet therapy lessened as platelet count decreased in patients with AIS with thrombocytopenia. However, our findings suggest that antiplatelet medications remain safe and effective for this population.
Impact of Chronic Kidney Disease on the Processes of Care and Long‐Term Mortality of Non–ST‐Segment–Elevation Myocardial Infarction: A Nationwide Cohort Study and Long‐Term Follow‐Up
Authors: Weight Nicholas , Moledina Saadiq , Ullah Mohsin , Wijeysundera Harindra C. , Davies Simon , Chew Nicholas W. S. , Lawson Claire , Khan Safi U. , Gale Chris P. , Rashid Muhammad , Mamas Mamas A. 
Published: August 2024

Background
A growing population of patients with chronic kidney disease (CKD) presents with non–ST‐segment–elevation myocardial infarction, although little is known about their longer‐term mortality.

Methods and Results

Using the MINAP (Myocardial Ischaemia National Audit Project) registry, linked to Office for National Statistics mortality data, we analyzed 363 559 UK patients with non–ST‐segment–elevation myocardial infarction, with or without CKD. Cox regression models were fitted, adjusting for baseline demographics. Compared with patients without CKD, patients with CKD were less frequently prescribed P2Y12 inhibitors (89% versus 86%,
P
<0.001) less likely to undergo invasive angiography (67% versus 41%,
P
<0.001) or percutaneous coronary intervention (41% versus 25%,
P
<0.001), and were less often referred to cardiac rehabilitation (80% versus 66%,
P
<0.001). Following non–ST‐segment–elevation myocardial infarction, patients with CKD had higher risk of 30‐day (adjusted hazard ratio [HR], 1.24 [95% CI, 1.20–1.29], 1‐year 1.47 [95% CI, 1.44–1.51]) and 5‐year mortality 1.55 (95% CI, 1.53–1.58) than patients without CKD (all
P
<0.001). Risk of mortality over the entire study period was highest in CKD Stage 5 (HR, 2.98 [95% CI, 2.87–3.10]), even after excluding mortality ≤30 days (HR, 3.03 [95% CI, 2.90–3.17]) (
P
<0.001). There was no significant difference in proportion of deaths attributable to cardiovascular disease at 30 days (CKD; 76% versus no CKD; 76%), or 1 ‐year (CKD; 62% versus no CKD; 62%).

Conclusions
Patients with CKD were significantly less likely to receive invasive investigation or undergo percutaneous coronary intervention and had significantly higher risk of short‐ and longer‐term mortality. Risk of mortality increased with reducing CKD stage. Cardiovascular disease was the main cause of mortality in patients with CKD, but at comparable rates to the general population with non–ST‐segment–elevation myocardial infarction.
Physician‐Reported Facilitators and Barriers for Side Effect Management of Heart Failure Medications
Authors: Mangal Sabrina , Hyder Maryam , Mancini John , Zarzuela Kate , McDonald William , Safford Monika , Lachs Mark , Goyal Parag 
Published: August 2024

Background
Physician underprescribing and patient nonadherence are major barriers to the benefits of guideline‐directed medical therapy. An important contributor to both underprescribing and patient nonadherence is concern about medication‐related side effects. Yet, there are few to no data on approaches used by physicians to: (1) elicit medication‐related side effects, (2) attribute these side effects to specific medications, and (3) take appropriate action.

Methods and Results
The authors conducted semistructured interviews with physicians to identify facilitators and barriers to each critical step of heart failure medication management: elicitation of side effects, attribution of side effects to a medication, and action in response to attributed side effects. Interviews were transcribed and coded using directed content analysis. For elicitation of potential side effects, limited patient communication and family discordance in reporting were key barriers, whereas guiding questions, measurement, and open channels of communication were key facilitators. For attribution of side effects, confounding from other medications, limited time for clinical encounters, and nonspecific symptoms were key barriers, whereas time‐limited medication discontinuation trials and medication rechallenges were key facilitators. For taking action, challenges with weighing risks and benefits and physician fear about causing harm or interfering with other clinicians were barriers, whereas patient‐physician communication and the results of a medication discontinuation trials and medication rechallenge were facilitators.

Conclusions
This study generated key facilitators and barriers to 3 key aspects of heart failure medication management related to side effects that should drive future work to improve heart failure medication management.
Treatment Adherence Rates and Long‐Term Mortality in a Quaternary Multidisciplinary Heart Team: An Observational Cohort
Authors: McNamara David A. , Akram Mahrukh F. , Burgess Andrea L. , Stickland DeeAnn , VanOosterhout Stacie M. , Parker Jessica L. , Madder Ryan D. , Wohns David , Willekes Charles L. , McNamara Richard F. 
Published: August 2024

Background
A multidisciplinary heart team (HT) approach to patients with complex coronary artery disease has a class IB recommendation, yet there are limited data on adherence to HT treatment recommendations and long‐term clinical follow‐up. The objective of this study was to assess adherence rates to HT recommendations and assess long‐term mortality rates among patients with complex CAD.

Methods and Results
Six hundred eighty‐four sequential HT cases for complex coronary artery disease from January 2015 to May 2017 were reviewed. After excluding cases with significant comorbid valve disease, baseline characteristics were compared based on HT treatment recommendations: optimal medical therapy, percutaneous coronary intervention, and coronary artery bypass grafting. Adherence rates were manually extracted, and 5‐year mortality rates were obtained from the Michigan Death Registry. Seventy‐two percent of 405 included patients were men (mean age 66±11 years), with high rates of medical comorbidities. Estimated surgical risk scores were lowest in the coronary artery bypass grafting group. Optimal medical therapy was recommended in 138 patients (34%), percutaneous coronary intervention in 95 (23%), and coronary artery bypass grafting in 172 (42%). Adherence to HT recommendations across groups was high (96%) and did not differ between treatment groups. Over 5 years of follow‐up, there were 119 deaths, resulting in a cumulative mortality rate of 29%.

Conclusions
In the largest HT cohort in the United States to date, high rates of adherence to HT recommendations were observed among high‐risk patients with coronary artery disease. High rates of adherence to HT recommendations were observed irrespective of treatment group recommendation, suggesting that HT recommendations were individualized and acceptable to both patients and physicians alike.
Cardiovascular Risks in People With Narcolepsy: Expert Panel Consensus Recommendations
Authors: Kwon Younghoon , Gami Apoor S. , Javaheri Shahrokh , Pressman Gregg S. , Scammell Thomas E. , Surkin Lee A. , Zee Phyllis C. 
Published: August 2024

Background
Observational and retrospective studies suggest that people with narcolepsy may have an increased prevalence of cardiovascular and cardiometabolic comorbidities and may be at greater risk for future cardiovascular events. An expert consensus panel was formed to establish agreement on the risk of hypertension and cardiovascular/cardiometabolic disease in people with narcolepsy and to develop strategies to mitigate these risks.

Methods and Results
Experts in sleep medicine and cardiology were selected to participate in the panel. After reviewing the relevant literature, the experts identified key elements, drafted recommendation statements, and developed discussion points to provide supporting evidence for the recommendations. The draft and final recommendations were rated on a scale from 0 (not at all agree) to 4 (very much agree). All experts had an agreement rating of 4.0 for all 14 revised recommendation statements for patients with narcolepsy. These statements comprised 3 themes: (1) recognize the risk of hypertension and cardiovascular/cardiometabolic disease, (2) reduce the risk of hypertension and cardiovascular/cardiometabolic disease, and (3) reduce sodium intake to lower the risk of hypertension and cardiovascular disease.

Conclusions
These consensus recommendations are intended to increase awareness of potential cardiovascular/cardiometabolic risks in patients with narcolepsy for all clinicians. Early monitoring for, and prevention of, cardiovascular risks in this population are of great importance, especially as narcolepsy usually develops in adolescents and young adults, who will be exposed to adverse effects of the disease for decades. Prospective systematic studies are needed to determine association and causation of narcolepsy with cardiovascular/cardiometabolic disorders.
LifeCourse Socioeconomic Position and Ideal Cardiovascular Health in Hispanic/Latino Adults of the Hispanic Community Health Study/Study of Latinos
Authors: Filigrana Paola , Moon Jee‐Young , Gallo Linda C. , Fernández‐Rhodes Lindsay , Perreira Krista M. , Daviglus Martha L. , Thyagarajan Bharat , Garcia‐Bedoya Olga L. , Cai Jianwen , Xue Xiaonan , Kaplan Robert C. , Suglia Shakira , Isasi Carmen R. 
Published: August 2024

Background
The Hispanic/Latino population experiences socioeconomic disadvantages across the lifespan. Yet, little is known about the role of these disadvantages in cardiovascular health (CVH). We assessed the association of lifecourse socioeconomic position (SEP) with ideal CVH and change in Hispanic/Latino adults.

Methods and Results
We used longitudinal data from the HCHS/SOL (Hispanic Community Health Study/Study of Latinos). Childhood SEP was determined using parental educational attainment. Adult SEP was determined through an index combining participants' education, occupation, income, and assets at baseline. We classified participants into 4 socioeconomic mobility categories (eg, stable low or high SEP, upward or downward mobility). Using the 4 health factors of the American Heart Association “Life's Essential 8,” we built a score of ideal CVH at baseline and the 6‐year follow‐up. Linear mixed‐effects models using inverse probability weighting were fitted to assess the main associations. Higher childhood SEP was associated with higher ideal CVH at baseline (β for high school versus <high school, 3.57 [95% CI, 1.76–5.57]) and (>high school versus <high school, 3.76 [95% CI, 1.99–5.52]). Middle (β for middle versus low SEP, 3.57 [95% CI, 1.65–5.49]) and high adult SEP (β for high versus low SEP, 5.05 [95% CI, 2.55–7.55]) were also associated with higher ideal CVH. Socioeconomic mobility was also associated with higher ideal CVH. No life‐course SEP exposure was associated with the change in ideal CVH over a 6‐year period.

Conclusions
Although high childhood and adult SEP and socioeconomic mobility were associated with higher levels of ideal CVH, they were not associated with change in ideal‐CVH.
Monocyte Chemoattractant Protein‐1, Inflammatory Biomarkers, and Prognosis of Patients With Ischemic Stroke or Transient Ischemic Attack: Fndings From a Nationwide Registry Study
Authors: Xu Qin , Liu Yuanliang , Tian Xue , Xia Xue , Zhang Yijun , Zhang Xiaoli , Wang Yongjun , Sun Ping , Meng Xia , Wang Anxin 
Published: August 2024

Background
Recent Mendelian randomization and meta‐analysis highlight the relevance of MCP‐1 (monocyte chemoattractant protein‐1) in stroke. We aimed to investigate the associations between MCP‐1 and clinical outcomes in patients with ischemic stroke or transient ischemic attack and test whether inflammation mediates or jointly contributes to the relationships.

Methods and Results
A total of 10 700 patients from the Third China National Stroke Registry study were included. Multivariable Cox regression was used for recurrent stroke and all‐cause death, and logistic regression was used for poor functional outcome. Mediation analyses were performed to clarify whether inflammation mediates the associations. After adjusting for potential confounders, low MCP‐1 level (<337.6 pg/mL) was associated with a reduced risk of all‐cause death (hazard ratio [HR], 0.65 [95% CI, 0.51–0.82]) and poor functional outcome (odds ratio, 0.81 [95% CI, 0.70–0.94]) but was not associated with recurrent stroke (HR, 1.10 [95% CI, 0.95–1.27]), compared with high MCP‐1 level (≥337.6 pg/mL). The association between MCP‐1 and all‐cause death was partially mediated by highly sensitive C‐reactive protein, interleukin‐6, and YKL‐40 (Chitinase‐3‐like protein 1; mediated proportion: 7.4%, 10.5%, and 7.4%, respectively). The corresponding mediated proportion for poor functional outcome was 9.9%, 17.1%, and 7.1%, respectively. Patients with combined high levels of MCP‐1 and inflammatory biomarkers had the highest risks of all‐cause death and poor functional outcome.

Conclusions
Low plasma MCP‐1 level was associated with decreased risks of all‐cause mortality and poor functional outcome after ischemic stroke or transient ischemic attack. Inflammation partially mediated and jointly contributed to the associations.
Semiquantitative assessment of phosphatase and tensin homolog value with immunohistochemistry in colorectal cancer
Authors: Jeo Wifanto S. , Lalisang Toar J.M. , Siregar Nurjati C. , Sudoyo Aru W. , Pakasi Trevino , Jusman Sri W. , Asmarinah Asmarinah 
Published: August 2024

Introduction Colorectal cancer has emerged as a concerning health problem, ranking the third most common form of cancer in both men and women. The phosphatase and tensin homologue (PTEN) protein is widely known for its role as an inhibitor of the phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, playing a major role inhibiting tumor development. Previous studies investigated the role of this protein in the PI3K pathway and how it affected colorectal cancer. However, a standardized cut-off value for PTEN expression has not been established. Methods Immunohistochemistry was used in examining PTEN. The staining grade ranging from 0 to 3 was then multiplied by the number of 100 cancer cells counted, with total score between 0 and 300. In this study, receiver operating characteristic (ROC) curve was employed to determine the expression cut-off value for PTEN in colorectal cancer. Results This study showed statistically significant results ( P < 0.001) in either tumor or non-tumor tissues by using the ROC curve with a cut-off value of 199.0. This study also revealed significant correlation between nodal status with PTEN ( P = 0.008) and stage with PTEN ( P = 0.019) with sensitivity 0.753 and specificity 0.728. Conclusion Semiquantitative assessment with cell counting multiplied by color intensity is a good method in determining PTEN expression. The use of immunohistochemical staining intensity and cell scoring with ROC cut-off is effective to elaborate the effects of PTEN in colorectal cancer (PTEN value > 199.0 was classified as strong and ≤ 199.0 as weak).