bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cdkn2a Loss in a Model of Neurofibroma Demonstrates Stepwise Tumor Progression to Atypical Neurofibroma and MPNST
Authors: Chaney Katherine E. , Perrino Melissa R. , Kershner Leah J. , Patel Ami V. , Wu Jianqiang , Choi Kwangmin , Rizvi Tilat A. , Dombi Eva , Szabo Sara , Largaespada David A. , Ratner Nancy 
Published: August 2020

Abstract

Plexiform neurofibromas are benign nerve sheath Schwann cell tumors characterized by biallelic mutations in the neurofibromatosis type 1 (NF1) tumor suppressor gene. Atypical neurofibromas show additional frequent loss of CDKN2A/Ink4a/Arf and may be precursor lesions of aggressive malignant peripheral nerve sheath tumors (MPNST). Here we combined loss of Nf1 in developing Schwann cells with global Ink4a/Arf loss and identified paraspinal plexiform neurofibromas and atypical neurofibromas. Upon transplantation, atypical neurofibromas generated genetically engineered mice (GEM)-PNST similar to human MPNST, and tumors showed reduced p16INK4a protein and reduced senescence markers, confirming susceptibility to transformation. Superficial GEM-PNST contained regions of nerve-associated plexiform neurofibromas or atypical neurofibromas and grew rapidly on transplantation. Transcriptome analyses showed similarities to corresponding human tumors. Thus, we recapitulated nerve tumor progression in NF1 and provided preclinical platforms for testing therapies at each tumor grade. These results support a tumor progression model in which loss of NF1 in Schwann cells drives plexiform neurofibromas formation, additional loss of Ink4a/Arf contributes to atypical neurofibromas formation, and further changes underlie transformation to MPNST.

Significance:
New mouse models recapitulate the stepwise progression of NF1 tumors and will be useful to define effective treatments that halt tumor growth and tumor progression in NF1.
Cross-talk between SOX2 and TGFβ Signaling Regulates EGFR–TKI Tolerance and Lung Cancer Dissemination
Authors: Kuo Ming-Han , Lee An-Chun , Hsiao Shih-Hsin , Lin Sey-En , Chiu Yu-Fan , Yang Li-Hao , Yu Chia-Cherng , Chiou Shih-Hwa , Huang Hsien-Neng , Ko Jen-Chung , Chou Yu-Ting 
Published: August 2020

Abstract

Regulation of the stemness factor, SOX2, by cytokine stimuli controls self-renewal and differentiation in cells. Activating mutations in EGFR are proven therapeutic targets for tyrosine kinase inhibitors (TKI) in lung adenocarcinoma, but acquired resistance to TKIs inevitably occurs. The mechanism by which stemness and differentiation signaling emerge in lung cancers to affect TKI tolerance and lung cancer dissemination has yet to be elucidated. Here, we report that cross-talk between SOX2 and TGFβ signaling affects lung cancer cell plasticity and TKI tolerance. TKI treatment favored selection of lung cancer cells displaying mesenchymal morphology with deficient SOX2 expression, whereas SOX2 expression promoted TKI sensitivity and inhibited the mesenchymal phenotype. Preselection of EGFR-mutant lung cancer cells with the mesenchymal phenotype diminished SOX2 expression and TKI sensitivity, whereas SOX2 silencing induced vimentin, but suppressed BCL2L11, expression and promoted TKI tolerance. TGFβ stimulation downregulated SOX2 and induced epithelial-to-mesenchymal transdifferentiation accompanied by increased TKI tolerance, which can interfere with ectopic SOX2 expression. SOX2-positive lung cancer cells exhibited a lower dissemination capacity than their SOX2-negative counterparts. Tumors expressing low SOX2 and high vimentin signature were associated with worse survival outcomes in patients with EGFR mutations. These findings provide insights into how cancer cell plasticity regulated by SOX2 and TGFβ signaling affects EGFR-TKI tolerance and lung cancer dissemination.

Significance:
These findings suggest the potential of SOX2 as a prognostic marker in EGFR-mutant lung cancer, as SOX2-mediated cell plasticity regulated by TGFβ stimulation and epigenetic control affects EGFR-TKI tolerance and cancer dissemination.
Morphology-Predicted Large-Scale Transition Number in Circulating Tumor Cells Identifies a Chromosomal Instability Biomarker Associated with Poor Outcome in Castration-Resistant Prostate Cancer
Authors: Schonhoft Joseph D. , Zhao Jimmy L. , Jendrisak Adam , Carbone Emily A. , Barnett Ethan S. , Hullings Melanie A. , Gill Audrey , Sutton Ramsay , Lee Jerry , Dago Angel E. , Landers Mark , Bakhoum Samuel F. , Wang Yipeng , Gonen Mithat , Dittamore Ryan , Scher Howard I. 
Published: August 2020

Abstract

Chromosomal instability (CIN) increases a tumor cell's ability to acquire chromosomal alterations, a mechanism by which tumor cells evolve, adapt, and resist therapeutics. We sought to develop a biomarker of CIN in circulating tumor cells (CTC) that are more likely to reflect the genetic diversity of patient's disease than a single-site biopsy and be assessed rapidly so as to inform treatment management decisions in real time. Large-scale transitions (LST) are genomic alterations defined as chromosomal breakages that generate chromosomal gains or losses of greater than or equal to10 Mb. Here we studied the relationship between the number of LST in an individual CTC determined by direct sequencing and morphologic features of the cells. This relationship was then used to develop a computer vision algorithm that utilizes CTC image features to predict the presence of a high (9 or more) versus low (8 or fewer) LST number in a single cell. As LSTs are a primary functional component of homologous recombination deficient cellular phenotypes, the image-based algorithm was studied prospectively on 10,240 CTCs in 367 blood samples obtained from 294 patients with progressing metastatic castration-resistant prostate cancer taken prior to starting a standard-of-care approved therapy. The resultant computer vision-based biomarker of CIN in CTCs in a pretreatment sample strongly associated with poor overall survival times in patients treated with androgen receptor signaling inhibitors and taxanes.

Significance:
A rapidly assessable biomarker of chromosomal instability in CTC is associated with poor outcomes when detected in men with progressing mCRPC.
Change of Health‐Related Quality of Life Over Time and Its Association With Patient Outcomes in Patients With Heart Failure
Authors: Sepehrvand Nariman , Savu Anamaria , Spertus John A. , Dyck Jason R. B. , Anderson Todd , Howlett Jonathan , Paterson Ian , Oudit Gavin Y , Kaul Padma , McAlister Finlay A. , Ezekowitz Justin A. ,   the Alberta HEART Investigators*
Published: August 2020

Background
Improving health‐related quality of life is an important goal in the management of patients with heart failure (HF). Defining health‐related quality of life changes over time in patients with HF with preserved (HFpEF) or reduced ejection fraction and showing their association with other important clinical events could support the use of health‐related quality of life as a measure of quantifying HF care.

Methods and Results

In the Alberta HEART (Heart Failure Aetiology and Analysis Team) cohort (n=621), patients were categorized into 4 subgroups: healthy controls (n=98), at risk (n=163), HFpEF (n=191), and HF with reduced ejection fraction (n=169). The change of the Kansas City Cardiomyopathy Questionnaire (KCCQ), EuroQOL 5 dimensions, and Functional Assessment of Cancer Therapy—Anemia over 12 months, and its association with a composite of death or rehospitalization within 3 years were assessed. At baseline, the KCCQ overall summary score was 73 (interquartile range, 53–86) in HFpEF and 78 (interquartile range, 56–90) in HF with reduced ejection fraction (
P
=0.22). Overall, 30.5% of patients with HF experienced ≥5‐point improvements and 32.4% had ≥5‐point worsening in KCCQ overall summary score at 12 months, which did not differ between HFpEF and HF with reduced ejection fraction (
P
=0.23). Clinical events were higher in patients with HF who had a decline in KCCQ over 12 months as compared with those with stable KCCQ scores (70.2% versus 52.0%,
P
=0.012). The results were similar for the Functional Assessment of Cancer Therapy—Anemia and EuroQOL 5 dimensions.

Conclusions
In patients with HF, the KCCQ quantified clinically meaningful changes over time, which were associated with important clinical outcomes in patients with HFpEF. Given the observed variability and prognostication in different patient trajectories, health‐related quality of life measures could be valuable for quantifying the quality of care in healthcare systems.
Extreme Phenotype Approach Suggests Taste Transduction Pathway for Carotid Plaque in a Multi-Ethnic Cohort
Authors: Dueker Nicole D. , Doliner Brett , Gardener Hannah , Dong Chuanhui , Beecham Ashley , Della-Morte David , Sacco Ralph L. , Blanton Susan H. , Wang Liyong , Rundek Tatjana 
Published: August 2020

Background and Purpose:
Carotid plaque is a heritable trait and a strong predictor of vascular events. Several loci have been identified for carotid plaque, however, studies in minority populations are lacking. Within a multi-ethnic cohort, we have identified individuals with extreme total carotid plaque area (TCPA), that is, higher or lower TCPA than expected based on traditional vascular risk factors (age, sex, smoking, diabetes mellitus, hypertension, etc). We hypothesized that these individuals are enriched with genetic variants accounting for the plaque burden that cannot be explained by traditional vascular risk factors. Herein, we sought to identify the genetic basis for TCPA using the multi-ethnic cohort.

Methods:

Three hundred forty participants (170 from each extreme group) from 3 race/ethnic groups (53% Hispanic, 29% non-Hispanic Black, and 18% non-Hispanic White) were genotyped using a genome-wide single-nucleotide polymorphism (SNP) array and imputed using 1000Genome data. SNP-based analyses using logistic regression and gene-based analyses using VEGAS2 were performed within each race/ethnic group and then meta-analyzed. Genes with
P
<0.001 were included in an overrepresentation enrichment pathway analysis using WebGestalt. Promising findings were tested for association with ischemic stroke using the MEGASTROKE Consortium data set.

Results:

No SNP or gene reached genome-wide significance. In the pathway analysis, GO:0050913 (sensory perception of bitter taste) gene set was significantly enriched (
P
=4.5×10
−6
, false discovery rate=0.04), which was confirmed in MEGASTROKE (
P
=0.01). Within the GO:0050913 gene set, 3 genes were associated with extreme TCPA in our study (
P
<0.001):
TAS2R20
,
TAS2R50
, and
ITPR3
. In
TAS2R50
, rs1376251 is the top SNP and has been associated with myocardial infarction by others. In
ITPR3
, a SNP with high regulatory potential (rs3818527, RegulomeScore=1f), and
ITPR3
itself were among the top SNP-based and gene-based results and showed consistent evidence for association in all ethnic groups (
P
<0.05).

Conclusions:
Extreme TCPA analysis identified new candidate genes for carotid plaque in understudied populations.
Higher Doses Improve Walking Recovery During Stroke Inpatient Rehabilitation
Authors: Klassen Tara D. , Dukelow Sean P. , Bayley Mark T. , Benavente Oscar , Hill Michael D. , Krassioukov Andrei , Liu-Ambrose Teresa , Pooyania Sepideh , Poulin Marc J. , Schneeberg Amy , Yao Jennifer , Eng Janice J. 
Published: August 2020

Background and Purpose:
We investigated the effect of higher therapeutic exercise doses on walking during inpatient rehabilitation, typically commencing 1 to 4 weeks poststroke.

Methods:
This phase II, blinded-assessor, randomized controlled trial recruited from 6 Canadian inpatient rehabilitation units, between 2014 and 2018. Subjects (n=75; 25/group) were randomized into: control (usual care) physical therapy: typically, 1 hour, 5 days/week; Determining Optimal Post-Stroke Exercise (DOSE1): 1 hour, 5 days/week, more than double the intensity of Control (based on aerobic minutes and walking steps); and DOSE2: 2 hours, 5 days/week, more than quadruple the intensity of Control, each for 4 weeks duration. The primary outcome, walking endurance at completion of the 4-week intervention (post-evaluation), was compared across these groups using linear regression. Secondary outcomes at post-evaluation, and longitudinal outcomes at 6 and 12-month evaluations, were also analyzed.

Results:

Both DOSE1 (mean change 61 m [95% CI, 9–113],
P
=0.02) and DOSE2 (mean change 58 m, 6–110,
P
=0.03) demonstrated greater walking endurance compared with Control at the post-evaluation. Significant improvements were also observed with DOSE2 in gait speed (5-m walk), and both DOSE groups in quality of life (EQ-5D-5 L) compared with Control. Longitudinal analyses revealed that improvements in walking endurance from the DOSE intervention were retained during the 1-year follow-up period over usual care.

Conclusions:
This study provides the first preliminary evidence that patients with stroke can improve their walking recovery and quality of life with higher doses of aerobic and stepping activity within a critical time period for neurological recovery. Furthermore, walking endurance benefits achieved from a 4-week intervention are retained over the first-year poststroke.

Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01915368.
Twenty-Year Time Trends in Long-Term Case-Fatality and Recurrence Rates After Ischemic Stroke Stratified by Etiology
Authors: Rücker Viktoria , Heuschmann Peter U. , O’Flaherty Martin , Weingärtner Michael , Hess Manuela , Sedlak Claudia , Schwab Stefan , Kolominsky-Rabas Peter L. 
Published: August 2020

Background and Purpose:
Data on long-term survival and recurrence after stroke are lacking. We investigated time trends in ischemic stroke case-fatality and recurrence rates over 20-years stratified by etiological subtype according to the Trial of ORG 10172 in Acute Stroke Treatment classification within a population-based stroke register in Germany.

Methods:
Data was collected within the Erlangen Stroke Project, a prospective, population-based stroke register covering a source population of 105 164 inhabitants (2010). Case fatality and recurrence rates for 3 months, 1 year, and 5 years were estimated with Kaplan-Meier estimates. Sex-specific time trends for case-fatality and recurrence rates were estimated with Cox regression. We adjusted for age, sex, and year of event and stratified for etiological subtypes. A sensitivity analysis with competing risk analysis for time trends in recurrence were performed.

Results:
Between 1996 and 2015, 3346 patients with first ischemic stroke were included; age-standardized incidence per 100 000 was 75.8 in women and 131.6 in men (2015). Overall, 5-year survival probabilities were 50.4% (95% CI, 47.9–53.1) in women and 59.2% (95% CI, 56.4–62.0) in men; 5-year survival was highest in patients with first stroke due to small-artery occlusion (women, 71.8% [95% CI, 67.1–76.9]; men, 75.9% [95% CI, 71.3–80.9]) and lowest in cardioembolic stroke (women, 35.7% [95% CI, 31.0–41.1]; men, 47.8% [95% CI, 42.2–54.3]). Five-year recurrence rates were 20.1% (95% CI, 17.5–22.6) in women and 20.1% (95% CI, 17.5–22.7) in men; 5-year recurrence rate was lowest in women in stroke due to small artery occlusion 16.0% (95% CI, 11.7–20.1) and in men in large-artery atherosclerosis 16.6% (95% CI, 8.7–23.9); highest risk of recurrence was observed in undefined strokes (women, 22.3% [95% CI, 17.8–26.6]; men, 21.4% [95% CI, 16.7–25.9]). Cox regression revealed improvements in case-fatality rates over time with differences in stroke causes. No time trends in recurrence rates were observed.

Conclusions:
Long-term survival and recurrence varied substantially by first stroke cause. Survival probabilities improved over the past 2 decades; no major trends in stroke recurrence rates were observed.
Etiological Subtypes of Transient Ischemic Attack and Ischemic Stroke in Chronic Kidney Disease
Authors: Kelly Dearbhla M. , Li Linxin , Rothwell Peter M. ,   on behalf of the Oxford Vascular Study
Published: August 2020

Background and Purpose:
Chronic kidney disease (CKD) is strongly associated with stroke risk, but the mechanisms underlying this association are unclear and might be informed by subtype-specific analyses. However, few studies have reported stroke subtypes in CKD according to established classification systems, such as the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria. We, therefore, aimed to determine which transient ischemic attack and ischemic stroke subtypes using the TOAST classification occur most frequently in patients with CKD.

Methods:
In a population-based study of all transient ischemic attack and stroke (OXVASC [Oxford Vascular Study]; 2002–2017), all ischemic events were classified by TOAST subtypes (cardioembolism, large artery disease, small vessel disease, undetermined, multiple, other etiology, or incompletely investigated). Logistic regression was used to determine the relationship between CKD (defined as an estimated glomerular filtration rate <60 mL/min per 1.73 m2) and transient ischemic attack/stroke subtypes adjusted for age, sex, and hypertension and then stratified by age and estimated glomerular filtration rate category.

Results:

Among 3178 patients with transient ischemic attack (n=1167), ischemic stroke (n=1802), and intracerebral hemorrhage (n=209), 1267 (40%) had CKD. Although there was a greater prevalence of cardioembolic events (31.8% versus 21.2%;
P
<0.001) in patients with CKD, this association was lost after adjustment for age, sex, and hypertension (adjusted odds ratio=1.20 [95% CI, 0.99–1.45];
P
=0.07). Similarly, although patients with CKD had a lower prevalence of small vessel disease (8.8% versus 13.6%;
P
<0.001), undetermined (26.1% versus 39.4%;
P
<0.001), and other etiology (1.0% versus 3.6%;
P
<0.001) subtypes, these associations were also lost after adjustment (adjusted odds ratio=0.86 [0.65–1.13];
P
=0.27 and 0.73 [0.36–1.43];
P
=0.37 for small vessel disease and other defined etiology, respectively) for all but undetermined (adjusted odds ratio=0.81 [0.67–0.98];
P
=0.03).

Conclusions:
There were no independent positive associations between CKD and specific TOAST subtypes, which suggest that renal-specific risk factors are unlikely to play an important role in the etiology of particular subtypes. Future studies of stroke and CKD should report subtype-specific analyses to gain further insights into potential mechanisms.
Initial Stroke Severity in Patients With Atrial Fibrillation According to Antithrombotic Therapy Before Ischemic Stroke
Authors: Jung Yo Han , Kim Young Dae , Kim Jinkwon , Han Sang Won , Oh Mi Sun , Lee Ji Sung , Lee Kyung-Yul 
Published: August 2020

Background and Purpose:
Atrial fibrillation (AF) is the leading cause of ischemic stroke. Preventive antithrombotic use, especially for anticoagulation, reduces the incidence of ischemic stroke in patients with AF. Using data from the nationwide multicenter stroke registry, we investigated the trends of preceding antithrombotic medication use in patients with acute ischemic stroke (AIS) with AF and its association with initial stroke severity and in-hospital outcomes.

Methods:
This study included 6786 patients with AIS with known AF before stroke admission across 39 hospitals between June 2008 and December 2018. We collected the data on antithrombotic medication use (no antithrombotic/antiplatelet/anticoagulant) preceding AIS. Initial stroke severity was measured using the National Institutes of Health Stroke Scale, and in-hospital outcome was determined by modified Rankin Scale score at discharge.

Results:

During the study period, anticoagulant use continued to increase. However, nearly one-third of patients with AIS with known AF did not receive antithrombotics before stroke. Initial National Institutes of Health Stroke Scale scores varied according to preceding antithrombotic therapy (
P
<0.001). It was higher in patients who did not receive antithrombotics than in those who received antiplatelets or anticoagulants (median National Institutes of Health Stroke Scale score: 8 versus 7 and 8 versus 6, respectively). Favorable outcome at discharge (modified Rankin Scale score, 0–2) was more prevalent in patients who received antiplatelets or anticoagulants (
P
<0.001). Use of antiplatelets (odds ratio, 1.23 [95% CI, 1.09–1.38]) and anticoagulants (odds ratio, 1.31 [95% CI, 1.15–1.50]) was associated with a mild initial neurological deficit (National Institutes of Health Stroke Scale score ≤5) in patients with AIS with AF.

Conclusions:
Throughout the study period, the proportion of patients taking anticoagulants increased among patients with AIS with known AF. However, a large portion of AF patients still did not receive antithrombotics before AIS. Furthermore, prehospitalization use of anticoagulants was associated with a significantly higher likelihood of a mild initial neurological deficit and favorable outcome at discharge.
The Association Between Alcoholic Liver Disease and Alcohol Tax
Authors: Aslam Sadaf , Buggs Jacentha , Melo Samantha , Ermekbaeva Aizara , Rogers Ebonie , Shaw Robert , Kumar Ambuj , Kemmer Nyingi 
Published: August 2020

Background The incidence of alcoholic liver disease (ALD) has increased, causing it to become a primary indication for liver transplantation in the United States. We hypothesized an association between alcohol taxation and prevalence of ALD. Methods We conducted a retrospective study of united network for organ sharing (UNOS) waitlist additions for liver transplantation between January 2007 and December 2016. We also analyzed the average excise tax (2007-2016) for beer, wine, and spirits in listing states of liver transplant waitlist additions (LTWA). Results There were 104 805 adult UNOS LTWA with assigned diagnoses, an annual increase from 22% to 28%. There were 24 316 LTWA with ALD diagnosis. The mean value for beer tax was significantly lower for ALD patients than for non-ALD patients across all age groups ( P < .001). The analysis demonstrated significantly more ALD in waitlisted patients 35-54 years of age (30%), compared with 18-34 years (10%) and ≥55 years (20%), P < .001. The data confirmed significantly more ALD Medicaid patients in the 35-54 year age group (28%) compared with other age groups, P < .001. Discussion Our research demonstrated an association between lower beer tax and higher ALD prevalence across all age groups. We found a larger percentage of middle-aged (35-54 years) Medicaid patients listed with ALD. These findings raise the need for further investigation of a potential public health concern for an association between ALD and beer tax, especially for middle-aged patients of lower socioeconomic status.