bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigations on Piezoelectric, Dielectric and Mechanical Properties of PVDF/PVC/GO Nanocomposites
Authors: Sagar Rohan , Kumar Akash , Raghav Rajesh Kumar , Gaur M. S. 
Published: August 2023

In this study, the hardness of polyvinylidene fluoride (PVDF), PVC and PVDF/PVC/GO (2.0 wt%) was estimated using piezoelectric and dielectric properties. The structure morphology was analyzed by Fourier transform infrared spectroscopy (FTIR). With the help of the solution casting technique, GO nanofiller were incorporated into PVDF/PVC matrix to prepare nanocomposites. In the case of PVDF/PVC/GO nanocomposites (2.0 wt%), the d33 coefficient is comparatively higher. PVDF have lower dielectric constant, however, may be due to interfacial polarization occurring at the spherulites and at the polymer/filler interfaces. The achieved lower loss tangent (tanδ) for PVDF compared to PVDF/PVC and PVDF/PVC/GO (2.0 wt%) nanocomposites is attributed to PVDF highly insulating nature. The PVDF/PVC/GO (2.0 wt%) nanocomposite exhibited a d33 value of ∼26 pm V−1, which was significantly higher than pure PVDF and PVDF/PVC.
Fatty Acids Support the Fitness and Functionality of Tumor-Resident CD8+ T Cells by Maintaining SCML4 Expression
Authors: Feng Maoxiao , Liu Xiaoyan , Hao Xiaodong , Ren Yidan , Dong Guoying , Tian Jie , Wang Yuli , Du Lutao , Wang Yunshan , Wang Chuanxin 
Published: August 2023

Abstract

CD8+ tissue-resident memory T (Trm) cells and tumor-infiltrating lymphocytes (TIL) regulate tumor immunity and immune surveillance. Characterization of Trm cells and TILs could help identify potential strategies to boost antitumor immunity. Here, we found that the transcription factor SCML4 was required for the progression and polyfunctionality of Trm cells and was associated with a better prognosis in patients with cancer. Moreover, SCML4 maintained multiple functions of TILs. Increased expression of SCML4 in CD8+ cells significantly reduced the growth of multiple types of tumors in mice, while deletion of SCML4 reduced antitumor immunity and promoted CD8+ T-cell exhaustion. Mechanistically, SCML4 recruited the HBO1–BRPF2–ING4 complex to reprogram the expression of T cell–specific genes, thereby enhancing the survival and effector functions of Trm cells and TILs. SCML4 expression was promoted by fatty acid metabolism through mTOR–IRF4–PRDM1 signaling, and fatty acid metabolism–induced epigenetic modifications that promoted tissue-resident and multifunctional gene expression in Trm cells and TILs. SCML4 increased the therapeutic effect of anti–PD-1 treatment by elevating the expression of effector molecules in TILs and inhibiting the apoptosis of TILs, which could be further enhanced by adding an inhibitor of H3K14ac deacetylation. These results provide a mechanistic perspective of functional regulation of tumor-localized Trm cells and TILs and identify an important activation target for tumor immunotherapy.

Significance:
SCML4 upregulation in CD8+ Trm cells and tumor-infiltrating lymphocytes induced by fatty acid metabolism enhances antitumor immune responses, providing an immunometabolic axis to target for cancer treatment.
See related commentary by Chakraborty et al., p. 3321
CDK4/6 Inhibition Sensitizes Intracranial Tumors to PD-1 Blockade in Preclinical Models of Brain Metastasis
Authors: Nayyar Naema , de Sauvage Magali A. , Chuprin Jane , Sullivan Emily M. , Singh Mohini , Torrini Consuelo , Zhang Britney S. , Bandyopadhyay Sushobhana , Daniels Keith A. , Alvarez-Breckenridge Christopher , Dahal Ashish , Brehm Michael A. , Brastianos Priscilla K. 
Published: August 2023

Abstract

Purpose:
Brain metastases are associated with high morbidity and are often resistant to immune checkpoint inhibitors. We evaluated whether CDK4/6 inhibitor (CDKi) abemaciclib can sensitize intracranial tumors to programmed cell death protein 1 (PD-1) inhibition in mouse models of melanoma and breast cancer brain metastasis.

Experimental Design:
Treatment response was evaluated in vivo using immunocompetent mouse models of brain metastasis bearing concurrent intracranial and extracranial tumors. Treatment effect on intracranial and extracranial tumor–immune microenvironments (TIME) was evaluated using immunofluorescence, multiplex immunoassays, high-parameter flow cytometry, and T-cell receptor profiling. Mice with humanized immune systems were evaluated using flow cytometry to study the effect of CDKi on human T-cell development.

Results:
We found that combining abemaciclib with PD-1 inhibition reduced tumor burden and improved overall survival in mice. The TIME, which differed on the basis of anatomic location of tumors, was altered with CDKi and PD-1 inhibition in an organ-specific manner. Combination abemaciclib and anti–PD-1 treatment increased recruitment and expansion of CD8+ effector T-cell subsets, depleted CD4+ regulatory T (Treg) cells, and reduced levels of immunosuppressive cytokines in intracranial tumors. In immunodeficient mice engrafted with human immune systems, abemaciclib treatment supported development and maintenance of CD8+ T cells and depleted Treg cells.

Conclusions:
Our results highlight the distinct properties of intracranial and extracranial tumors and support clinical investigation of combination CDK4/6 and PD-1 inhibition in patients with brain metastases.
See related commentary by Margolin, p. 257
Negative Hyperselection of Patients with HER2+ and RAS Wild-Type Metastatic Colorectal Cancer Receiving Dual HER2 Blockade: the PRESSING-HER2 Study
Authors: Randon Giovanni , Nakamura Yoshiaki , Yaeger Rona , Lonardi Sara , Cremolini Chiara , Elez Elena , Nichetti Federico , Ghelardi Filippo , Nasca Vincenzo , Bergamo Francesca , Conca Veronica , Ros Javier , Bando Hideaki , Maddalena Giulia , Oldani Simone , Prisciandaro Michele , Raimondi Alessandra , Schrock Alexa B. , Agnelli Luca , Walch Henry , Yoshino Takayuki , Pietrantonio Filippo 
Published: August 2023

Abstract

Purpose:
To demonstrate the negative prognostic impact of a panel of genomic alterations (PRESSING-HER2 panel) and lack of HER2 amplification by next-generation sequencing (NGS) in patients with HER2+, RAS wild-type metastatic colorectal cancer receiving dual HER2 blockade.

Experimental Design:
The PRESSING-HER2 panel of HER2 mutations/rearrangements and RTK/MAPK mutations/amplifications was assessed by NGS. HER2 amplification was confirmed by NGS if copy-number variation (CNV) was ≥ 6. With a case–control design, hypothesizing 30% and 5% PRESSING-HER2 positivity in resistant [progression-free survival (PFS) &lt;4 months and no RECIST response] versus sensitive cohorts, respectively, 35 patients were needed per group.

Results:
PRESSING-HER2 alterations included HER2 mutations/rearrangements, EGFR amplification, and BRAF mutations and had a prevalence of 27% (9/33) and 3% (1/35) in resistant versus sensitive patients (P = 0.005) and 63% predictive accuracy. Overall, HER2 nonamplified status by NGS had 10% prevalence. Median PFS and overall survival (OS) were worse in PRESSING-HER2+ versus negative (2.2 vs. 5.3 months, P &lt; 0.001; 5.4 vs. 14.9 months, P = 0.001) and in HER2 nonamplified versus amplified (1.6 vs. 5.2 months, P &lt; 0.001; 7.4 vs. 12.4 months, P = 0.157). These results were confirmed in multivariable analyses [PRESSING-HER2 positivity: PFS HR = 3.06, 95% confidence interval (CI), 1.40–6.69, P = 0.005; OS HR = 2.93, 95% CI, 1.32–6.48, P = 0.007]. Combining PRESSING-HER2 and HER2 CNV increased the predictive accuracy to 75%.

Conclusions:
PRESSING-HER2 panel and HER2 nonamplified status by NGS warrant validation as potential predictive markers in this setting.
See related commentary by Raghav et al., p. 260
FDA Approval Summary: Dabrafenib in Combination with Trametinib for BRAFV600E Mutation–Positive Low-Grade Glioma
Authors: Barbato Michael I. , Nashed Jeannette , Bradford Diana , Ren Yi , Khasar Sachia , Miller Claudia P. , Zolnik Banu S. , Zhao Hong , Li Yangbing , Bi Youwei , Shord Stacy S. , Amatya Anup K. , Mishra-Kalyani Pallavi S. , Scepura Barbara , Al-Matari Raniya A. , Pazdur Richard , Kluetz Paul G. , Donoghue Martha , Singh Harpreet , Drezner Nicole 
Published: August 2023

Abstract
On March 16, 2023, the FDA approved dabrafenib in combination with trametinib (Tafinlar, Mekinist; Novartis Pharmaceuticals Corporation) for the treatment of pediatric patients with low-grade glioma (LGG) with a BRAFV600E mutation who require systemic therapy. FDA also approved oral formulations of both drugs suitable for patients who cannot swallow pills. This approval was based on the LGG cohort from study CDRB436G2201 (NCT02684058), a multicenter, open-label trial in which pediatric patients with LGG with a BRAFV600E mutation were randomly assigned 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V). The overall response rate (ORR) by independent review based on Response Assessment in Neuro-oncology LGG (2017) criteria was assessed in 110 patients randomly assigned to D+T (n = 73) or C+V (n = 37). ORR was 47% [95% confidence interval (CI), 35–59] in the D+T arm and 11% (95% CI, 3.0–25) in the C+V arm. Duration of response (DOR) was 23.7 months (95% CI, 14.5–NE) in the D+T arm and not estimable (95% CI, 6.6– NE) in the C+V arm. Progression-free survival (PFS) was 20.1 months (95% CI: 12.8, NE) and 7.4 months (95% CI, 3.6– 11.8) [HR, 0.31 (95% CI, 0.17–0.55); P &lt; 0.001] in the D+T and C+V arms, respectively. The most common (&gt;20%) adverse reactions were pyrexia, rash, headache, vomiting, musculoskeletal pain, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain, and dermatitis acneiform. This represents the first FDA approval of a systemic therapy for the first-line treatment of pediatric patients with LGG with a BRAFV600E mutation.
Short-Term DAPT and DAPT De-Escalation Strategies for Patients With Acute Coronary Syndromes: A Systematic Review and Network Meta-Analysis
Authors: Kuno Toshiki , Watanabe Atsuyuki , Shoji Satoshi , Fujisaki Tomohiro , Ueyama Hiroki , Takagi Hisato , Deharo Pierre , Cuisset Thomas , Bangalore Sripal , Mehran Roxana , Stone Gregg W. , Kohsaka Shun , Bhatt Deepak L. 
Published: August 2023

BACKGROUND:
Short-term (≤6 months) dual antiplatelet therapy (DAPT) and DAPT de-escalation become attractive for patients with acute coronary syndrome.

METHODS:

A systemic search identified randomized controlled trials that included patients with acute coronary syndrome treated using (1) standard DAPT (12 months) with clopidogrel, prasugrel (standard/low dose), or ticagrelor; (2) extended DAPT (≥18 months); (3) short-term DAPT (≤6 months) followed by P2Y
12
inhibitor or aspirin; (4) 12-month DAPT with unguided de-escalation from potent P2Y
12
inhibitors to low-dose potent P2Y
12
inhibitor or clopidogrel at 1 month; and (5) guided selection DAPT with genotype or platelet function tests. The primary efficacy outcome (major adverse cardiovascular events) was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major or minor bleeding.

RESULTS:

This meta-analysis included 32 randomized controlled trials with 103 497 patients. While there were no differences in efficacy between short, unguided de-escalation and guided selection strategies, unguided de-escalation was associated with reduced risk of major adverse cardiovascular events compared with standard DAPT with clopidogrel or ticagrelor (hazard ratio [95% CI], 0.67 [0.49–0.93] and 0.68 [0.50–0.93]). Both short DAPT followed by P2Y
12
inhibitor and unguided de-escalation were associated with reduced risks in safety compared with other strategies, including guided selection (hazard ratio [95% CI], 0.66 [0.47–0.93] and 0.48 [0.33–0.71]). Short DAPT followed by a P2Y
12
inhibitor was associated with reduced risk of major bleeding and all-cause death compared with standard, extended DAPT (eg, versus DAPT with clopidogrel; hazard ratio [95% CI], 0.64 [0.42–0.97] and 0.60 [0.44–0.82]). By rankogram, unguided de-escalation strategy was the safest and most effective strategy in reducing major adverse cardiovascular events and major or minor bleeding while short DAPT followed by P2Y
12
inhibitor was ranked the best for major bleeding and all-cause death.

CONCLUSIONS:

In patients with acute coronary syndrome, unguided de-escalation was associated with the lowest risk of major adverse cardiovascular events and major or minor bleeding outcomes, while short DAPT followed by P2Y
12
inhibitor was associated with the lowest risk of major bleeding and all-cause death.
Elevated Plasma Levels of Ketone Bodies Are Associated With All‐Cause Mortality and Incidence of Heart Failure in Older Adults: The CHS
Authors: Niezen Sebastian , Connelly Margery A. , Hirsch Calvin , Kizer Jorge R. , Benitez Maria E. , Minchenberg Scott , Perez‐Matos Maria Camila , Jiang Zhenghui Gordon , Mukamal Kenneth J. 
Published: August 2023

Background
Chronic disease, such as heart failure, influences cellular metabolism and shapes circulating metabolites. The relationships between key energy metabolites and chronic diseases in aging are not well understood. This study aims to determine the relationship between main components of energy metabolism with all‐cause mortality and incident heart failure.

Methods and Results

We analyzed the association between plasma metabolite levels with all‐cause mortality and incident heart failure among US older adults in the CHS (Cardiovascular Health Study). We followed 1758 participants without heart failure at baseline with hazard ratios (HRs) of analyte levels and metabolic profiles characterized by high levels of ketone bodies for all‐cause mortality and incident heart failure. Multivariable Cox analyses revealed a dose‐response relationship of 50% increase in all‐cause mortality between lowest and highest quintiles of ketone body concentrations (HR, 1.5 [95% CI, 1.0–1.9];
P
=0.007). Ketone body levels remained associated with incident heart failure after adjusting for cardiovascular disease confounders (HR, 1.2 [95% CI, 1.0–1.3];
P
=0.02). Using K‐means cluster analysis, we identified a cluster with higher levels of ketone bodies, citrate, interleukin‐6, and B‐type natriuretic peptide but lower levels of pyruvate, body mass index, and estimated glomerular filtration rate. The cluster with elevated ketone body levels was associated with higher all‐cause mortality (HR, 1.7 [95% CI, 1.1–2.7];
P
=0.01).

Conclusions
Higher concentrations of ketone bodies predict incident heart failure and all‐cause mortality in an older US population, independent of metabolic and cardiovascular confounders. This association suggests a potentially important relationship between ketone body metabolism and aging.
Type 2 Diabetes and Atrial Fibrillation: Evaluating Causal and Pleiotropic Pathways Using Mendelian Randomization
Authors: Reddy Rohin K. , Ardissino Maddalena , Ng Fu Siong 
Published: August 2023

Background
Observational associations between type 2 diabetes (T2D) and atrial fibrillation (AF) have been established, but causality remains undetermined. We performed Mendelian randomization (MR) to study causal effects of genetically predicted T2D on AF risk, independent of cardiometabolic risk factors.

Methods and Results

Instrumental variables included 182 uncorrelated single nucleotide polymorphisms associated with T2D at genome‐wide significance (
P
<5×10
−8
). Genetic association estimates for cardiometabolic exposures were obtained from genome‐wide association studies including 188 577 individuals for low‐density lipoprotein‐C, 694 649 individuals for body mass index, and 757 601 for systolic blood pressure. Two‐sample, inverse‐variance weighted MR formed the primary analyses. The MR‐TRYX approach was used to dissect potential pleiotropic pathways, with multivariable MR performed to investigate cardiometabolic mediation. Genetically predicted T2D associated with increased AF liability in univariable MR (odds ratio [OR], 1.08 [95% CI, 1.02–1.13],
P
=0.003). Sensitivity analyses indicated potential pleiotropy, with radial MR identifying 4 outlier single nucleotide polymorphisms that were likely contributors. Phenomic scanning on MR‐base and subsequent least absolute shrinkage and selection operator regression allowed prioritization of 7 candidate traits. The outlier‐adjusted effect estimate remained consistent with the original inverse‐variance weighted estimate (OR, 1.07 [95% CI, 1.02–1.12],
P
=0.008). On multivariable MR, T2D remained associated with increased AF liability after adjustment for low‐density lipoprotein‐C and body mass index. Following adjustment for systolic blood pressure, the relationship between T2D and AF became nonsignificant (OR, 1.04 [95% CI, 0.95–1.13],
P
=0.40).

Conclusions
These data provide novel genetic evidence that while T2D likely causally associates with AF, mediation via systolic blood pressure exists. Endeavoring to lower systolic blood pressure alongside achieving normoglycemia may provide particular benefit on AF risk in patients with T2D.
Carotid Plaque Score for Stroke and Cardiovascular Risk Prediction in a Middle‐Aged Cohort From the General Population
Authors: Ihle‐Hansen Håkon , Vigen Thea , Berge Trygve , Walle‐Hansen Marte M. , Hagberg Guri , Ihle‐Hansen Hege , Thommessen Bente , Ariansen Inger , Røsjø Helge , Rønning Ole Morten , Tveit Arnljot , Lyngbakken Magnus 
Published: August 2023

Background
We aimed to explore the predictive value of the carotid plaque score, compared with the Systematic Coronary Risk Evaluation 2 (SCORE2) risk prediction algorithm, on incident ischemic stroke and major adverse cardiovascular events and establish a prognostic cutoff of the carotid plaque score.

Methods and Results
In the prospective ACE 1950 (Akershus Cardiac Examination 1950 study), carotid plaque score was calculated with ultrasonography at inclusion in 2012 to 2015. The largest plaque diameter in each extracranial segment of the carotid artery on both sides was scored from 0 to 3 points. The sum of points in all segments provided the carotid plaque score. The cohort was followed up by linkage to national registries for incident ischemic stroke and major adverse cardiovascular events (nonfatal ischemic stroke, nonfatal myocardial infarction, and cardiovascular death) throughout 2020. Carotid plaque score was available in 3650 (98.5%) participants, with mean±SD age of 63.9±0.64 years at inclusion. Only 462 (12.7%) participants were free of plaque, and and 970 (26.6%) had a carotid plaque score of >3. Carotid plaque score predicted ischemic stroke (hazard ratio [HR], 1.25 [95% CI, 1.15–1.36]) and major adverse cardiovascular events (HR, 1.21 [95% CI, 1.14–1.27]) after adjustment for SCORE2 and provided strong incremental prognostic information to SCORE2. The best cutoff value of carotid plaque score for ischemic stroke was >3, with positive predictive value of 2.5% and negative predictive value of 99.3%.

Conclusions
The carotid plaque score is a strong predictor of ischemic stroke and major adverse cardiovascular events, and it provides incremental prognostic information to SCORE2 for risk prediction. A cutoff score of >3 seems to be suitable to discriminate high‐risk subjects.

Registration Information
clinicaltrials.gov. Identifier: NCT01555411.
Spreading Depolarizations Suppress Hematoma Growth in Hyperacute Intracerebral Hemorrhage in Mice
Authors: Fischer Paul , Tamim Isra , Sugimoto Kazutaka , Morais Andreia , Imai Takahiko , Takizawa Tsubasa , Qin Tao , Schlunk Frieder , Endres Matthias , Yaseen Mohammad A. , Chung David Y. , Sakadzic Sava , Ayata Cenk 
Published: August 2023

BACKGROUND:
Spreading depolarizations (SDs) occur in all types of brain injury and may be associated with detrimental effects in ischemic stroke and subarachnoid hemorrhage. While rapid hematoma growth during intracerebral hemorrhage triggers SDs, their role in intracerebral hemorrhage is unknown.

METHODS:
We used intrinsic optical signal and laser speckle imaging, combined with electrocorticography, to investigate the effects of SD on hematoma growth during the hyperacute phase (0–4 hours) after intracortical collagenase injection in mice. Hematoma expansion, SDs, and cerebral blood flow were simultaneously monitored under normotensive and hypertensive conditions.

RESULTS:

Spontaneous SDs erupted from the vicinity of the hematoma during rapid hematoma growth. We found that hematoma growth slowed down by >60% immediately after an SD. This effect was even stronger in hypertensive animals with faster hematoma growth. To establish causation, we exogenously induced SDs (every 30 minutes) at a remote site by topical potassium chloride application and found reduced hematoma growth rate and final hemorrhage volume (18.2±5.8 versus 10.7±4.1 mm
3
). Analysis of cerebral blood flow using laser speckle flowmetry revealed that suppression of hematoma growth by spontaneous or induced SDs coincided and correlated with the characteristic oligemia in the wake of SD, implicating the vasoconstrictive effect of SD as one potential mechanism of action.

CONCLUSIONS:
Our findings reveal that SDs limit hematoma growth during the early hours of intracerebral hemorrhage and decrease final hematoma volume.
Richness and endemism in Chusquea subg. Swallenochloa (Poaceae), a Neotropical subgenus adapted to temperate conditions
Authors: RUIZ-SANCHEZ EDUARDO , MUNGUÍA-LINO GUADALUPE , PIANISSOLA EVANDRO MACHADO , ELY FRANCISCA , CLARK LYNN G. 
Published: August 2023

Chusquea subg. Swallenochloa comprises 52 species distributed in five biogeographical areas (Mexican Transition Zone, Brazilian subregion, South American Transition Zone, Chacoan subregion, and Andean region). Species of the subgenus grow from almost sea level in the Andean region to almost 4000 m in the northern South American Transition Zone (SATZ) and are often common or dominant elements of the vegetation. In this study, three questions related to species richness, endemism, and risk category of Chusquea subg. Swallenochloa were addressed. Analyses were based on the geo-referenced occurrence data of these 52 species, using different methods and software programs. Results indicate that the Chacoan subregion and SATZ had the highest richness with 16 and 15 species, respectively. The area of highest endemism was found in the Brazilian subregion. The AOO and EOO methods provided strongly differing estimations of conservation status.