bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Combined Proteomics and Mendelian Randomization Approach to Investigate the Effects of Aspirin-Targeted Proteins on Colorectal Cancer
Authors: Nounu Aayah , Greenhough Alexander , Heesom Kate J. , Richmond Rebecca C. , Zheng Jie , Weinstein Stephanie J. , Albanes Demetrius , Baron John A. , Hopper John L. , Figueiredo Jane C. , Newcomb Polly A. , Lindor Noralane M. , Casey Graham , Platz Elizabeth A. , Le Marchand Loïc , Ulrich Cornelia M. , Li Christopher I. , van Duijnhoven Fränzel J.B. , Gsur Andrea , Campbell Peter T. , Moreno Víctor , Vodicka Pavel , Vodickova Ludmila , Brenner Hermann , Chang-Claude Jenny , Hoffmeister Michael , Sakoda Lori C. , Slattery Martha L. , Schoen Robert E. , Gunter Marc J. , Castellví-Bel Sergi , Kim Hyeong Rok , Kweon Sun-Seog , Chan Andrew T. , Li Li , Zheng Wei , Bishop D. Timothy , Buchanan Daniel D. , Giles Graham G. , Gruber Stephen B. , Rennert Gad , Stadler Zsofia K. , Harrison Tabitha A. , Lin Yi , Keku Temitope O. , Woods Michael O. , Schafmayer Clemens , Van Guelpen Bethany , Gallinger Steven , Hampel Heather , Berndt Sonja I. , Pharoah Paul D.P. , Lindblom Annika , Wolk Alicja , Wu Anna H. , White Emily , Peters Ulrike , Drew David A. , Scherer Dominique , Bermejo Justo Lorenzo , Williams Ann C. , Relton Caroline L. 
Published: January 2021

Abstract

Background:
Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk.

Methods:
Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N = 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N = 31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls).

Results:
Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2, and ARFIP2 expression, and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR: 1.08, 95% CI, 1.03–1.13; OR: 3.33, 95% CI, 2.46–4.50; and OR: 1.15, 95% CI, 1.02–1.29, respectively).

Conclusions:
MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation, indicating a possible role in aspirin's reduction of metastasis.

Impact:
Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.
Hysterectomy, Oophorectomy, and Risk of Renal Cell Carcinoma
Authors: Luo Juhua , Rohan Thomas E. , Neuhouser Marian L. , Liu Nianjun , Saquib Nazmus , Li Yueyao , Shadyab Aladdin H. , Qi Lihong , Wallace Robert B. , Hendryx Michael 
Published: January 2021

Abstract

Background:
Female hormones may play roles during renal cell carcinoma (RCC) carcinogenesis. The aims of this study were to investigate associations between hysterectomy, oophorectomy, and risk of RCC and to assess whether the associations were modified by exogenous estrogen, commonly used among women who have undergone hysterectomy.

Methods:
Postmenopausal women (n = 144,599) ages 50–79 years at enrollment (1993–1998) in the Women's Health Initiative were followed for a mean of 15.9 years. Hysterectomy and oophorectomy were self-reported. Incident RCC cases were confirmed by physician review of medical records and pathology reports. Multivariable Cox proportional hazards modeling was used to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusting for potential confounders.

Results:
A total of 583 women developed RCC during follow-up. We observed that hysterectomy, regardless of oophorectomy status, was significantly associated with an increased risk of RCC (HR, 1.28; 95% CI, 1.03–1.60). The association appeared to be more pronounced in women with age at hysterectomy younger than 40 years (HR, 1.34; 95% CI, 1.01–1.80) or older than 55 years (HR, 1.52; 95% CI, 1.01–2.29). Oophorectomy was not significantly associated with risk of RCC. There was no evidence that exogenous estrogen use modified the association between hysterectomy and risk of RCC.

Conclusions:
In this large prospective study, we showed that women with a history of hysterectomy had 28% increased risk of RCC, and this finding was not modified by exogenous hormone use.

Impact:
If our findings are confirmed, women should be made aware of increased risk of RCC when considering hysterectomy.
Therapeutic Implications of Detecting MAPK-Activating Alterations in Cutaneous and Unknown Primary Melanomas
Authors: Shoushtari Alexander N. , Chatila Walid K. , Arora Arshi , Sanchez-Vega Francisco , Kantheti Havish S. , Rojas Zamalloa Jorge A. , Krieger Penina , Callahan Margaret K. , Betof Warner Allison , Postow Michael A. , Momtaz Parisa , Nair Suresh , Ariyan Charlotte E. , Barker Christopher A. , Brady Mary Susan , Coit Daniel G. , Rosen Neal , Chapman Paul B. , Busam Klaus J. , Solit David B. , Panageas Katherine S. , Wolchok Jedd D. , Schultz Nikolaus 
Published: January 2021

Abstract

Purpose:
Cutaneous and unknown primary melanomas frequently harbor alterations that activate the MAPK pathway. Whether MAPK driver detection beyond BRAF V600 is clinically relevant in the checkpoint inhibitor era is unknown.

Experimental Design:
Patients with melanoma were prospectively offered tumor sequencing of 341–468 genes. Oncogenic alterations in 28 RTK-RAS-MAPK pathway genes were used to construct MAPK driver groups. Time to treatment failure (TTF) was determined for patients who received first-line programmed cell death protein 1 (PD-1) monotherapy, nivolumab plus ipilimumab, or subsequent genomically matched targeted therapies. A Cox proportional hazards model was constructed for TTF using driver group and clinical variables.

Results:
A total of 670 of 696 sequenced melanomas (96%) harbored an oncogenic RTK-RAS-MAPK pathway alteration; 33% had ≥1 driver. Nine driver groups varied by clinical presentation and mutational burden. TTF of PD-1 monotherapy (N = 181) varied by driver, with worse outcomes for NRAS Q61 and BRAF V600 versus NF1 or other alterations (median 4.2, 7.5, 22, and not reached; P &lt; 0.0001). Driver group remained significant, independent of tumor mutational burden and clinical features. TTF did not vary by driver for nivolumab plus ipilimumab (N = 141). Among 172 patients with BRAF V600 wild-type melanoma who progressed on checkpoint blockade, 27 were treated with genomically matched therapy, and eight (30%) derived clinical benefit lasting ≥6 months.

Conclusions:
Targeted capture multigene sequencing can detect oncogenic RTK-RAS-MAPK pathway alterations in almost all cutaneous and unknown primary melanomas. TTF of PD-1 monotherapy varies by mechanism of ERK activation. Oncogenic kinase fusions can be successfully targeted in immune checkpoint inhibitor–refractory melanoma.
Targeting BET Proteins BRD2 and BRD3 in Combination with PI3K-AKT Inhibition as a Therapeutic Strategy for Ovarian Clear Cell Carcinoma
Authors: Shigeta Shogo , Lui Goldie Y.L. , Shaw Reid , Moser Russell , Gurley Kay E. , Durenberger Grace , Rosati Rachele , Diaz Robert L. , Ince Tan A. , Swisher Elizabeth M. , Grandori Carla , Kemp Christopher J. 
Published: January 2021

Abstract
Ovarian clear cell carcinoma (OCCC) is a rare, chemo-resistant subtype of ovarian cancer. To identify novel therapeutic targets and combination therapies for OCCC, we subjected a set of patient-derived ovarian cancer cell lines to arrayed high-throughput siRNA and drug screening. The results indicated OCCC cells are vulnerable to knockdown of epigenetic gene targets such as bromodomain and extra-terminal domain (BET) proteins BRD2 and BRD3. Subsequent RNA interference assays, as well as BET inhibitor treatments, validated these BET proteins as potential therapeutic targets. Because development of resistance to single targeted agents is common, we next performed sensitizer drug screens to identify potential combination therapies with the BET inhibitor CPI0610. Several PI3K or AKT inhibitors were among the top drug combinations identified and subsequent work showed CPI0610 synergized with alpelisib or MK2206 by inducing p53-independent apoptosis. We further verified synergy between CPI0610 and PI3K–AKT pathway inhibitors alpelisib, MK2206, or ipatasertib in tumor organoids obtained directly from patients with OCCC. These findings indicate further preclinical evaluation of BET inhibitors, alone or in combination with PI3K-AKT inhibitors for OCCC, is warranted.
The Role of Forkhead Box Q1 Transcription Factor in Anticancer Effects of Withaferin A in Breast Cancer
Authors: Kim Su-Hyeong , Singh Krishna B. , Hahm Eun-Ryeong , Singh Shivendra V. 
Published: January 2021

Abstract

Elimination of both rapidly dividing epithelial mammary cancer cells as well as breast cancer stem-like cells (bCSC) is essential for maximizing antitumor response. Withaferin A (WA), a small molecule derived from a medicinal plant (Withania somnifera), is highly effective in reducing burden and/or incidence of breast cancer in vivo in various preclinical models. We have shown previously that suppression of breast cancer incidence by WA administration in a rat model is associated with a decrease in self-renewal of bCSC but the underlying mechanism is still elusive. This study investigated the role of forkhead box Q1 (FoxQ1) transcription factor in antitumor responses to WA. Exposure of MDA-MB-231 and SUM159 cells to WA resulted in downregulation of protein and mRNA levels of FoxQ1 as well as inhibition of its transcriptional activity. FoxQ1 overexpression in SUM159 and MCF-7 cells resulted in a marked protection against WA-mediated inhibition of bCSC as judged by flow cytometric analysis of CD49fhigh population and mammosphere assay. RNA-sequencing analysis revealed upregulation of many bCSC-associated genes by FoxQ1 overexpression in SUM159 cells, including IL8 whose expression was decreased by WA treatment in SUM159 and MCF-7 cells. FoxQ1 was recruited to the promoter of IL8 that was inhibited significantly by WA treatment. On the other hand, WA-mediated inhibition of cell proliferation or migration was not affected by FoxQ1 overexpression. The FoxQ1 overexpression partially attenuated WA-mediated G2–M phase cell cycle arrest in SUM159 cells only. These results indicate that FoxQ1 is a target of WA for inhibition of bCSC fraction.

Prevention Relevance:
Withaferin A (WA) is highly effective in reducing burden and/or incidence of breast cancer in various preclinical models. However, the mechanism underlying breast cancer prevention by WA is not fully understood. This study shows a role for FoxQ1 in antitumor response to WA.
Clements e o conceito de clímax
Authors: Martins Tatiane Barbosa , Martins Lilian Al-Chueyr Pereira 
Published: January 2021

Frederic Edward Clements (1874-1945), botânico norte-americano, deixou contribuições para a ecologia durante as quatro primeiras décadas do século XX. A ele é atribuída a proposta de conceitos como sucessão ecológica e clímax. O objetivo deste artigo é discutir sobre o percurso que levou Clements ao conceito de clímax no período compreendido entre 1904 e 1936. Além disso, esclarecer como esta contribuição foi recebida pela comunidade científica na época. Esta pesquisa levou à conclusão de que o termo clímax, ou mesmo sua conotação, não surgiram de imediato nas publicações de Clements (1904; 1905). Eles só apareceram a partir de 1916 (Clements, 1916) e estão intimamente relacionados com outras concepções suas como associação e organismo complexo, presentes em trabalhos anteriores (Clementes, 1904; Clements, 1905). Clements se baseou em estudos de campo e laboratório e em contribuições de outros autores. Não detectamos mudanças significativas em relação ao conceito de clímax entre 1916 e 1936. Ocorreu apenas a adição de mais detalhes e um refinamento das explicações anteriores. Quanto à recepção por parte da comunidade científica da época, pode-se dizer que as críticas foram dirigidas principalmente à restrição do clímax a aspectos climáticos e sua relação com a ideia de organismo complexo.
Telomerase as a Therapeutic Target in Cardiovascular Disease
Authors: Hoffmann Jedrzej , Richardson Gavin , Haendeler Judith , Altschmied Joachim , Andrés Vicente , Spyridopoulos Ioakim 
Published: January 2021

Shortened telomeres have been linked to numerous chronic diseases, most importantly coronary artery disease, but the underlying mechanisms remain ill defined. Loss-of-function mutations and deletions in telomerase both accelerate telomere shortening but do not necessarily lead to a clinical phenotype associated with atherosclerosis, questioning the causal role of telomere length in cardiac pathology. The differential extranuclear functions of the 2 main components of telomerase, telomerase reverse transcriptase and telomerase RNA component, offer important clues about the complex relationship between telomere length and cardiovascular pathology. In this review, we critically discuss relevant preclinical models, genetic disorders, and clinical studies to elucidate the impact of telomerase in cardiovascular disease and its potential role as a therapeutic target. We suggest that the antioxidative function of mitochondrial telomerase reverse transcriptase might be atheroprotective, making it a potential target for clinical trials.

Graphic Abstract:
A graphic abstract is available for this article.
Conventional and Novel Lipid Measures and Risk of Peripheral Artery Disease
Authors: Kou Minghao , Ding Ning , Ballew Shoshana H. , Salameh Maya J. , Martin Seth S. , Selvin Elizabeth , Heiss Gerardo , Ballantyne Christie M. , Matsushita Kunihiro , Hoogeveen Ron C. 
Published: January 2021

Objective:
The aim of this study was to comprehensively assess the association of multiple lipid measures with incident peripheral artery disease (PAD).

Approach and Results:

We used Cox proportional hazards models to characterize the associations of each of the fasting lipid measures (total cholesterol, LDL-C [low-density lipoprotein cholesterol], HDL-C [high-density lipoprotein cholesterol], triglycerides, RLP-C [remnant lipoprotein cholesterol], LDL-TG [LDL-triglycerides], sdLDL-C [small dense LDL-C], and Apo-E-HDL [Apo-E-containing HDL-C]) with incident PAD identified by pertinent
International Classification of Diseases, Ninth Revision, Clinical Modification
(
ICD-9-CM
) hospital discharge codes (eg, 440.2) among 8330 Black and White ARIC (Atherosclerosis Risk in Communities) participants (mean age 62.8 [SD 5.6] years) free of PAD at baseline (1996–1998) through 2015. Since lipid traits are biologically correlated to each other, we also conducted principal component analysis to identify underlying components for PAD risk. There were 246 incident PAD cases with a median follow-up of 17 years. After accounting for potential confounders, the following lipid measures were significantly associated with PAD (hazard ratio per 1-SD increment [decrement for HDL-C and Apo-E-HDL]): triglycerides, 1.21 (95% CI, 1.08–1.36); RLP-C, 1.18 (1.08–1.29); LDL-TG, 1.18 (1.05–1.33); HDL-C, 1.39 (1.16–1.67); and Apo-E-HDL, 1.27 (1.07–1.51). The principal component analysis identified 3 components (1: mainly loaded by triglycerides, RLP-C, LDL-TG, and sdLDL-C; 2: by HDL-C and Apo-E-HDL; and 3: by LDL-C and RLP-C). Components 1 and 2 showed independent associations with incident PAD.

Conclusions:
Triglyceride-related and HDL-related lipids were independently associated with incident PAD, which has implications on preventive strategies for PAD. However, none of the novel lipid measures outperformed conventional ones.

Graphic Abstract:
A graphic abstract is available for this article.
Characteristics and Outcomes of Elderly Patients With Hypertrophic Cardiomyopathy
Authors: Alashi Alaa , Smedira Nicholas G. , Popovic Zoran B. , Fava Agostina , Thamilarasan Maran , Kapadia Samir R. , Wierup Per , Lever Harry M. , Desai Milind Y. 
Published: January 2021

Background
We report characteristics and outcomes of elderly patients with hypertrophic cardiomyopathy (HCM) with basal septal hypertrophy and dynamic left ventricular outflow tract obstruction.

Methods and Results

We studied 1110 consecutive elderly patients with HCM (excluding moderate or greater aortic stenosis or subaortic membrane, age 80±5 years [range, 75–92 years], 66% women), evaluated at our center between June 2002 and December 2018. Clinical and echocardiographic data, including maximal left ventricular outflow tract gradient, were recorded. The primary outcome was death and appropriate internal defibrillator discharge. Hypertension was observed in 72%, with a Society of Thoracic Surgeons (STS) score (8.6±6); while 80% had no HCM‐related sudden cardiac death risk factors. Left ventricular mass index, basal septal thickness, and maximal left ventricular outflow tract gradient were 127±43 g/m
2
, 1.7±0.4 cm, and 49±31 mm Hg, respectively. A total of 597 (54%) had a left ventricular outflow tract gradient >30 mm Hg, of which 195 (33%) underwent septal reduction therapy (SRT; 79% myectomy and 21% alcohol ablation). At 5.1±4 years, 556 (50%) had composite events (273 [53%] in nonobstructive, 220 [55%] in obstructive without SRT, and 63 [32%] in obstructive subgroup with SRT). One‐ and 5‐year survival, respectively were 93% and 63% in nonobstructive, 90% and 63% in obstructive subgroup without SRT, and 94% and 84% in the obstructive subgroup with SRT. Following SRT, there were 5 (2.5%) in‐hospital deaths (versus an expected Society of Thoracic Surgeons mortality of 9.2%).

Conclusions
Elderly patients with HCM have a high prevalence of traditional cardiovascular rather than HCM risk factors. Longer‐term outcomes of the obstructive SRT subgroup were similar to a normal age‐sex matched US population.
Impact of Intracerebral Hematoma Evacuation During Decompressive Hemicraniectomy on Functional Outcomes
Authors: Li Luyuan , Molian Vaelan A. , Seaman Scott C. , Zanaty Mario , Howard Matthew A. , Greenlee Jeremy D. , Hasan David M. , Leira Enrique C. 
Published: January 2021

Background and Purpose:
Decompressive hemicraniectomy has been used to treat spontaneous intracerebral hemorrhage, but the benefit of evacuating the hematoma during the procedure is unclear. We aim to evaluate the utility of performing clot evacuation during hemicraniectomy for spontaneous intracerebral hemorrhage.

Methods:
Retrospective cohort of consecutive patients (2010–2019) treated with decompressive hemicraniectomy for a spontaneous supratentorial intracerebral hemorrhage at the University of Iowa. We compared hemicraniectomy alone to hemicraniectomy plus hematoma evacuation. We analyzed clinical features and hematoma characteristics. The outcomes at 6 months were dichotomized into unfavorable (Glasgow Outcome Scale score 1–3) and favorable (Glasgow Outcome Scale score 4–5).

Results:

Eighty-three patients underwent decompressive hemicraniectomy for spontaneous intracerebral hemorrhage, 52 with hematoma evacuation, and 31 without hematoma evacuation. There were no statistically significant differences in clinical and radiographic characteristics between the 2 groups. Evacuating the hematoma in addition to hemicraniectomy did not change the odds of favorable outcome at 6 months (
P
=0.806).

Conclusions:
In this retrospective study, the performance of hematoma evacuation during decompressive hemicraniectomy for spontaneous intracerebral hemorrhage may not change functional outcomes over performing the hemicraniectomy alone.
Patterns of Neointima Formation After Coil or Stent Treatment in a Rat Saccular Sidewall Aneurysm Model
Authors: Grüter Basil E. , Wanderer Stefan , Strange Fabio , Boillat Gwendoline , Täschler Dominik , Rey Jeannine , Croci Davide M. , Grandgirard Denis , Leib Stephen L. , von Gunten Michael , Di Santo Stefano , Widmer Hans Rudolf , Remonda Luca , Andereggen Lukas , Nevzati Edin , Coluccia Daniel , Fandino Javier , Marbacher Serge 
Published: January 2021

Background and Purpose:
Endovascular aneurysm treatment relies on a biological process, including cell migration for thrombus organization and growth of a neointima. To better understand aneurysm healing, our study explores the origin of neointima-forming and thrombus-organizing cells in a rat saccular sidewall aneurysm model.

Methods:
Saccular aneurysms were transplanted onto the abdominal aorta of male Lewis rats and endovascularly treated with coils (n=28) or stents (n=26). In 34 cases, GFP+ (green fluorescent protein)-expressing vital aneurysms were sutured on wild-type rats, and in 23 cases, decellularized wild-type aneurysms were sutured on GFP+ rats. Follow-up at 3, 7, 14, 21, and 28 days evaluated aneurysms by fluorescence angiography, macroscopic inspection, and microscopy for healing and inflammation status. Furthermore, the origin of cells was tracked with fluorescence histology.

Results:

In animals with successful functional healing, histological studies showed a gradually advancing thrombus organization over time characterized by progressively growing neointima from the periphery of the aneurysm toward the center. Cell counts revealed similar distributions of GFP+ cells for coil or stent treatment in the aneurysm wall (54.4% versus 48.7%) and inside the thrombus (20.5% versus 20.2%) but significantly more GFP+ cells in the neointima of coiled (27.2 %) than stented aneurysms (10.4%;
P
=0.008).

Conclusions:
Neointima formation and thrombus organization are concurrent processes during aneurysm healing. Thrombus-organizing cells originate predominantly in the parent artery. Neointima formation relies more on cell migration from the aneurysm wall in coiled aneurysms but receives greater contributions from cells originating in the parent artery in stent-treated aneurysms. Cell migration, which allows for a continuous endothelial lining along the parent artery’s lumen, may be a prerequisite for complete aneurysm healing after endovascular therapy. In terms of translation into clinical practice, these findings may explain the variability in achieving complete aneurysm healing after coil treatment and the improved healing rate in stent-assisted coiling.
Explaining Extreme Events of 2019 from a Climate Perspective
Authors: Herring Stephanie C. , Christidis Nikolaos , Hoell Andrew , Hoerling Martin P. , Stott Peter A. 
Published: January 2021

AbstractEditors note: For easy download the posted pdf of the Explaining Extreme Events of 2019 is a very low-resolution file. A high-resolution copy of the report is available by clicking here. Please be patient as it may take a few minutes for the high-resolution file to download.