bluuebunny/crossref_metadata_2025_split huggingface dataset:
FDA Approval Summary: Lurbinectedin for the Treatment of Metastatic Small Cell Lung Cancer
Authors: Singh Sonia , Jaigirdar Adnan A. , Mulkey Flora , Cheng Joyce , Hamed Salaheldin S. , Li Yangbing , Liu Jiang , Zhao Hong , Goheer Anwar , Helms Whitney S. , Wang Xing , Agarwal Rajiv , Pragani Rajan , Korsah Kwadwo , Tang Shenghui , Leighton John , Rahman Atiqur , Beaver Julia A. , Pazdur Richard , Theoret Marc R. , Singh Harpreet 
Published: December 2020

Abstract
On June 15, 2020, the FDA granted accelerated approval to lurbinectedin for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. Approval was granted on the basis of the clinically meaningful effects on overall response rate (ORR) and duration of response (DOR), and the safety profile observed in a multicenter, open-label, multicohort clinical trial (PM1183-B-005-14, NCT02454972), referred to as Study B-005, in patients with advanced solid tumors. The trial included a cohort of 105 patients with metastatic SCLC who had disease progression on or after platinum-based chemotherapy. The confirmed ORR determined by investigator assessment using RECIST 1.1 in the approved SCLC patient population was 35% [95% confidence interval (CI): 26–45], with a median DOR of 5.3 (95% CI: 4.1–6.4) months. The drug label includes warnings and precautions for myelosuppression, hepatotoxicity, and embryo-fetal toxicity. This is the first drug approved by the FDA in over 20 years in the second line for patients with metastatic SCLC. Importantly, this approval includes an indication for patients who have platinum-resistant disease, representing an area of particular unmet need.
Hypoxic Induction of Exosome Uptake through Proteoglycan-Dependent Endocytosis Fuels the Lipid Droplet Phenotype in Glioma
Authors: Cerezo-Magaña Myriam , Christianson Helena C. , van Kuppevelt Toin H. , Forsberg-Nilsson Karin , Belting Mattias 
Published: December 2020

AbstractAs an adaptive response to hypoxic stress, aggressive tumors rewire their metabolic phenotype into increased malignant behavior through extracellular lipid scavenging and storage in lipid droplets (LD). However, the underlying mechanisms and potential lipid source retrieved in the hypoxic tumor microenvironment remain poorly understood. Here, we show that exosome-like extracellular vesicles (EV), known as influential messengers in the tumor microenvironment, may also serve anabolic functions by transforming hypoxic, patient-derived human glioblastoma cell lines into the LD+ phenotype. EVs were internalized via a hypoxia-sensitive, endocytic mechanism that fueled LD formation through direct lipid transfer, and independently of fatty acid synthase activity. EVs can enter cells through multiple and yet ill-defined pathways. On a mechanistic level, we found that hypoxia-mediated EV uptake depends on increased heparan sulfate proteoglycan (HSPG) endocytosis that preferentially followed the lipid raft pathway. The functional relevance of HSPG was evidenced by the reversal of EV-mediated LD loading by targeting of HSPG receptor function.Implications:Together, our data extend the multifaceted role of EVs in cancer biology by showing their LD-inducing capacity in hypoxic glioma cells. Moreover, these findings highlight a potential function for HSPG-mediated endocytosis as a salvage pathway for EV retrieval during tumor stress conditions.
The Heme-Regulated Inhibitor Pathway Modulates Susceptibility of Poor Prognosis B-Lineage Acute Leukemia to BH3-Mimetics
Authors: Smith Kaitlyn H. , Budhraja Amit , Lynch John , Roberts Kathryn , Panetta John C. , Connelly Jon P. , Turnis Meghan E. , Pruett-Miller Shondra M. , Schuetz John D. , Mullighan Charles G. , Opferman Joseph T. 
Published: December 2020

Abstract

Antiapoptotic MCL1 is one of the most frequently amplified genes in human cancers and elevated expression confers resistance to many therapeutics including the BH3-mimetic agents ABT-199 and ABT-263. The antimalarial, dihydroartemisinin (DHA) translationally represses MCL-1 and synergizes with BH3-mimetics. To explore how DHA represses MCL-1, a genome-wide CRISPR screen identified that loss of genes in the heme synthesis pathway renders mouse BCR-ABL+ B-ALL cells resistant to DHA-induced death. Mechanistically, DHA disrupts the interaction between heme and the eIF2α kinase heme-regulated inhibitor (HRI) triggering the integrated stress response. Genetic ablation of Eif2ak1, which encodes HRI, blocks MCL-1 repression in response to DHA treatment and represses the synergistic killing of DHA and BH3-mimetics compared with wild-type leukemia. Furthermore, BTdCPU, a small-molecule activator of HRI, similarly triggers MCL-1 repression and synergizes with BH3-mimetics in mouse and human leukemia including both Ph+ and Ph-like B-ALL. Finally, combinatorial treatment of leukemia bearing mice with both BTdCPU and a BH3-mimetic extended survival and repressed MCL-1 in vivo. These findings reveal for the first time that the HRI-dependent cellular heme-sensing pathway can modulate apoptosis in leukemic cells by repressing MCL-1 and increasing their responsiveness to BH3-mimetics. This signaling pathway could represent a generalizable mechanism for repressing MCL-1 expression in malignant cells and sensitizing them to available therapeutics.

Implications:
The HRI-dependent cellular heme-sensing pathway can modulate apoptotic sensitivity in leukemic cells by repressing antiapoptotic MCL-1 and increasing their responsiveness to BH3-mimetics.
Protein Arginine Methyltransferase 5 (PRMT5) and the ERK1/2 & PI3K Pathways: A Case for PRMT5 Inhibition and Combination Therapies in Cancer
Authors: Sapir Tzuriel , Shifteh David , Pahmer Moshe , Goel Sanjay , Maitra Radhashree 
Published: December 2020

AbstractThe ERK1/2 (RAS, RAF, MEK, ERK) and PI3K (PI3K, AKT, mTOR, PTEN) pathways are the chief signaling pathways for cellular proliferation, survival, and differentiation. Overactivation and hyperphosphorylation of the ERK1/2 & PI3K pathways is frequently observed in cancer and is associated with poor patient prognosis. While it is well known that genetic alterations lead to the dysregulation of the ERK1/2 & PI3K pathways, increasing evidence showcase that epigenetic alterations also play a major role in the regulation of the ERK1/2 & PI3K pathways. Protein Arginine Methyltransferase 5 (PRMT5) is a posttranslational modifier for multiple cellular processes, which is currently being tested as a therapeutic target for cancer. PRMT5 has been shown to be overexpressed in many types of cancers, as well as negatively correlated with patient survival. Numerous studies are indicating that as a posttranslational modifier, PRMT5 is extensively involved in regulating the ERK1/2 & PI3K pathways. In addition, a large number of in vitro and in vivo studies are demonstrating that PRMT5 inhibition, as well as PRMT5 and ERK1/2 & PI3K combination therapies, show significant therapeutic effects in many cancer types. In this review, we explore the vast interactions that PRMT5 has with the ERK1/2 & PI3K pathways, and we make the case for further testing of PRMT5 inhibition, as well as PRMT5 and ERK1/2 & PI3K combination therapies, for the treatment of cancer.
A Therapeutic Strategy for Preferential Targeting of TET2-Mutant and TET Dioxygenase–Deficient Cells in Myeloid Neoplasms
Authors: Guan Yihong , Tiwari Anand D. , Phillips James G. , Hasipek Metis , Grabowski Dale R. , Pagliuca Simona , Gopal Priyanka , Kerr Cassandra M. , Adema Vera , Radivoyevitch Tomas , Parker Yvonne , Lindner Daniel J. , Meggendorfer Manja , Abazeed Mohamed , Sekeres Mikkeal A. , Mian Omar Y. , Haferlach Torsten , Maciejewski Jaroslaw P. , Jha Babal K. 
Published: December 2020

Abstract

TET2 is frequently mutated in myeloid neoplasms. Genetic TET2 deficiency leads to skewed myeloid differentiation and clonal expansion, but minimal residual TET activity is critical for survival of neoplastic progenitor and stem cells. Consistent with mutual exclusivity of TET2 and neomorphic IDH1/2 mutations, here we report that IDH1/2 mutant–derived 2-hydroxyglutarate is synthetically lethal to TET dioxygenase–deficient cells. In addition, a TET-selective small-molecule inhibitor decreases cytosine hydroxymethylation and restricted clonal outgrowth of TET2 mutant but not normal hematopoietic precursor cells in vitro and in vivo. Although TET inhibitor phenocopied somatic TET2 mutations, its pharmacologic effects on normal stem cells are, unlike mutations, reversible. Treatment with TET inhibitor suppresses the clonal evolution of TET2-mutant cells in murine models and TET2-mutated human leukemia xenografts. These results suggest that TET inhibitors may constitute a new class of targeted agents in TET2-mutant neoplasia.

Significance:
Loss-of-function somatic TET2 mutations are among the most frequent lesions in myeloid neoplasms and associated disorders. Here we report a strategy for selective targeting of residual TET dioxygenase activity in TET-deficient clones that results in restriction of clonal evolution in vitro and in vivo.
See related video: https://aacrjournals.org/webinar-minimal-tet-activity-targetable-vulnerability-tet2-and-neomorphic-idh12-mutant
Associations Between Female Sex, Sarcomere Variants, and Clinical Outcomes in Hypertrophic Cardiomyopathy
Authors: Lakdawala Neal K. , Olivotto Iacopo , Day Sharlene M. , Han Larry , Ashley Euan A. , Michels Michelle , Ingles Jodie , Semsarian Christopher , Jacoby Daniel , Jefferies John L. , Colan Steven D. , Pereira Alexandre C. , Rossano Joseph W. , Wittekind Sam , Ware James S. , Saberi Sara , Helms Adam S. , Cirino Allison L. , Leinwand Leslie A. , Seidman Christine E. , Ho Carolyn Y. 
Published: December 2020

Background:
The impact of sex on phenotypic expression in hypertrophic cardiomyopathy (HCM) has not been well characterized in genotyped cohorts.

Methods:
Retrospective cohort study from an international registry of patients receiving care at experienced HCM centers. Sex-based differences in baseline characteristics and clinical outcomes were assessed.

Results:

Of 5873 patients (3788 genotyped), 2226 (37.9%) were women. At baseline, women were older (49.0±19.9 versus 42.9±18.4 years,
P
<0.001) and more likely to have pathogenic/likely pathogenic sarcomeric variants (HCM patients with a sarcomere mutation; 51% versus 43%,
P
<0.001) despite equivalent utilization of genetic testing. Age at diagnosis varied by sex and genotype despite similar distribution of causal genes. Women were 3.6 to 7.1 years older at diagnosis (
P
<0.02) except for patients with
MYH7
variants where age at diagnosis was comparable for women and men (n=492; 34.8±19.2 versus 33.3±16.8 years,
P
=0.39). Over 7.7 median years of follow-up, New York Heart Association III-IV heart failure was more common in women (hazard ratio, 1.87 [CI, 1.48–2.36],
P
<0.001), after controlling for their higher burden of symptoms and outflow tract obstruction at baseline, reduced ejection fraction, HCM patients with a sarcomere mutation, age, and hypertension. All-cause mortality was increased in women (hazard ratio, 1.50 [CI, 1.13–1.99],
P
<0.01) but neither implantable cardioverter-defibrillator utilization nor ventricular arrhythmia varied by sex.

Conclusions:
In HCM, women are older at diagnosis, partly modified by genetic substrate. Regardless of genotype, women were at higher risk of mortality and developing severe heart failure symptoms. This points to a sex-effect on long-term myocardial performance in HCM, which should be investigated further.
Economic Evaluation of Catheter Ablation of Atrial Fibrillation in Patients with Heart Failure With Reduced Ejection Fraction
Authors: Chew Derek S. , Loring Zak , Anand Jatin , Fudim Marat , Lowenstern Angela , Rymer Jennifer A. , Weimer Kristin E.D. , Atwater Brett D. , DeVore Adam D. , Exner Derek V. , Noseworthy Peter A. , Yancy Clyde W. , Mark Daniel B. , Piccini Jonathan P. 
Published: December 2020

Background:
Randomized clinical trials have demonstrated that catheter ablation for atrial fibrillation in patients with heart failure with reduced ejection fraction may improve survival and other cardiovascular outcomes.

Methods:
We constructed a decision-analytic Markov model to estimate the costs and benefits of catheter ablation and medical management in patients with symptomatic heart failure with reduced ejection fraction (left ventricular ejection fraction ≤35%) and atrial fibrillation over a lifetime horizon. Evidence from the published literature informed the model inputs, including clinical effectiveness data from meta-analyses. Probabilistic and deterministic sensitivity analyses were performed. A 3% discount rate was applied to both future costs and benefits. The primary outcome was the incremental cost-effectiveness ratio assessed from the US health care sector perspective.

Results:
Catheter ablation was associated with 6.47 (95% CI, 5.89–6.93) quality-adjusted life years (QALYs) and a total cost of $105 657 (95% CI, $55 311–$191 934; 2018 US dollars), compared with 5.30 (95% CI, 5.20–5.39) QALYs and $63 040 (95% CI, $37 624–$102 260) for medical management. The incremental cost-effectiveness ratio for catheter ablation compared with medical management was $38 496 (95% CI, $5583–$117 510) per QALY gained. Model inputs with the greatest variation on incremental cost-effectiveness ratio estimates were the cost of ablation and the effect of catheter ablation on mortality reduction. When assuming a more conservative estimate of the treatment effect of catheter ablation on mortality (hazard ratio of 0.86), the estimated incremental cost-effectiveness ratio was $74 403 per QALY gained. At a willingness-to-pay threshold of $100 000 per QALY gained, atrial fibrillation ablation was found to be economically favorable compared with medical management in 95% of simulations.

Conclusions:
Catheter ablation in patients with heart failure with reduced ejection fraction patients and atrial fibrillation may be considered economically attractive at current benchmarks for societal willingness-to-pay in the United States.
Association of Diagnostic Coding‐Based Frailty and Outcomes in Patients With Heart Failure: A Report From the Veterans Affairs Health System
Authors: Kohsaka Shun , Sandhu Alexander T. , Parizo Justin T. , Shoji Satoshi , Kumamamru Hiraku , Heidenreich Paul A. 
Published: December 2020

Background
The aim of this study was to determine whether frailty is associated with increased admission and mortality risk in the setting of heart failure.

Methods and Results

This retrospective cohort analysis included patients treated within the Veterans Affairs Health System who had
International Classification of Diseases, Ninth Revision
(
ICD‐9
) codes for heart failure on 2 or more dates over a 2‐year period. The clinical variables identifiable in claims data, such as demographic variables and markers of physical and cognitive dysfunction, were used to identify patients meeting the frailty phenotype. Of 388 785 extracted patients with coding of heart failure between 2015 and 2018, 163 085 patients (41.9%) with ejection fraction (EF) measurement were included in the present analysis (38.3% with reduced EF and 61.7% with preserved EF). There were 16 660 patients (10.2%) who were identified as frail (9.1% in heart failure with reduced EF and 10.9% in heart failure with preserved EF). Frail patients were older, more often depressed, and were likely to have been admitted in the previous year. One‐year all‐cause mortality rate was 9.7% and 28.1%, and admission rate was 58.1% and 79.5% for nonfrail and frail patients, respectively. Frailty was associated with mortality and admission risk compared with the nonfrail group (adjusted odds ratio [OR], 1.71; 95% CI, 1.65–1.77 for mortality; adjusted OR, 1.29; 95% CI, 1.24–1.34 for admission) independent of EF.

Conclusions
Frailty based on diagnostic coding was associated with particularly higher risk of mortality despite adjustment for known clinical variables. Our findings underscore the importance of nontraditional parameters in the prognostic assessment.
Global Fractional Flow Reserve Value Predicts 5‐Year Outcomes in Patients With Coronary Atherosclerosis But Without Ischemia
Authors: Fournier Stephane , Collet Carlos , Xaplanteris Panagiotis , Zimmermann Frederik M. , Toth Gabor G. , Tonino Pim A. L. , Pijls Nico H. J. , Colaiori Iginio , Di Gioia Giuseppe , Barbato Emanuele , Jüni Peter , Fearon William F. , De Bruyne Bernard 
Published: December 2020

Background
Global fractional flow reserve (FFR) (ie, the sum of the FFR values in the 3 major coronary arteries) is a physiologic correlate of global atherosclerotic burden. The objective of the present study was to investigate the value of global FFR in predicting long‐term clinical outcome of patients with stable coronary artery disease but no ischemia‐inducing stenosis.

Methods and Results

We studied major adverse cardiovascular events (MACEs: all‐cause death, myocardial infarction, and any revascularization) after 5 years in 1122 patients without significant stenosis (all FFR >0.80; n=275) or with at least 1 significant stenosis successfully treated by percutaneous coronary intervention (ie, post–percutaneous coronary intervention FFR >0.80; n=847). The patients were stratified into low, mid, or high tertiles of global FFR (≤2.80, 2.80–2.88, and ≥2.88). Patients in the lowest tertile of global FFR showed the highest 5‐year MACE rate compared with those in the mid or high tertile of global FFR (27.5% versus 22.0% and 20.9%, respectively; log‐rank
P
=0.040). The higher 5‐year MACE rate was mainly driven by a higher rate of revascularization in the low global FFR group (16.4% versus 11.3% and 11.8%, respectively; log‐rank
P
=0.038). In a multivariable model, an increase in global FFR of 0.1 unit was associated with a significant reduction in the rates of MACE (hazard ratio [HR], 0.988; 95% CI, 0.977–0.998;
P
=0.023), myocardial infarction (HR, 0.982; 95% CI, 0.966–0.998;
P
=0.032), and revascularization (HR, 0.985; 95% CI, 0.972–0.999;
P
=0.040).

Conclusions
Even in the absence of ischemia‐producing stenoses, patients with a low global FFR, physiologic correlate of global atherosclerotic burden, present a higher risk of MACE at 5‐year follow‐up.
Imaging Predictors of Neurologic Outcome After Pediatric Arterial Ischemic Stroke
Authors: Jiang Bin , Hills Nancy K. , Forsyth Rob , Jordan Lori C. , Slim Mahmoud , Pavlakis Steven G. , Freidman Neil , Dlamini Nomazulu , Farooq Osman , Li Ying , Zhu Guangming , Fullerton Heather , Wintermark Max , Lo Warren D. , Dowling M.M. , Benedict S.L. , Bernard T.J. , Fox C.K. , deVeber G. , Friedman N.R. , Lo W. , Ichord R.N. , Tan M. , Mackay M. , Kirton A. , Hernandez Chavez M.I. , Humphreys P. , Sultan S. , Rivkin M.J. , Yeh A. , Rafay M.F. , Titomanlio L. , Kovacevic G.S. , Yager J.Y. , Amlie-Lefond C. , Condie J. , Kneen R. , Bjornson B. , Pergami P. , Zou L.P. , Elbers J. , Abdalla A. , Chan A.K. , Carpenter J.L. , Wong V.C. , Kirkham F. 
Published: December 2020

Background and Purpose:
To assess whether initial imaging characteristics independently predict 1-year neurological outcomes in childhood arterial ischemic stroke patients.

Methods:
We used prospectively collected demographic and clinical data, imaging data, and 1-year outcomes from the VIPS study (Vascular Effects of Infection in Pediatric Stroke). In 288 patients with first-time stroke, we measured infarct volume and location on the acute magnetic resonance imaging studies and hemorrhagic transformation on brain imaging studies during the acute presentation. Neurological outcome was assessed with the Pediatric Stroke Outcome Measure. We used univariate and multivariable ordinal logistic regression models to test the association between imaging characteristics and outcome.

Results:
Univariate analysis demonstrated that infarcts involving uncinate fasciculus, angular gyrus, insular cortex, or that extended from cortex to the subcortical nuclei were significantly associated with poorer outcomes with odds ratios ranging from 1.95 to 3.95. All locations except the insular cortex remained significant predictors of poor outcome on multivariable analysis. When infarct volume was added to the model, the locations did not remain significant. Larger infarct volumes and younger age at stroke onset were significantly associated with poorer outcome, but the strength of the relationships was weak. Hemorrhagic transformation did not predict outcome.

Conclusions:
In the largest pediatric arterial ischemic stroke cohort collected to date, we showed that larger infarct volume and younger age at stroke were associated with poorer outcomes. We made the novel observation that the strength of these associations was modest and limits the ability to use these characteristics to predict outcome in children. Infarcts affecting specific locations were significantly associated with poorer outcomes in univariate and multivariable analyses but lost significance when adjusted for infarct volume. Our findings suggest that infarcts that disrupt critical networks have a disproportionate impact upon outcome after childhood arterial ischemic stroke.
External Validation of Five Scores to Predict Stroke-Associated Pneumonia and the Role of Selected Blood Biomarkers
Authors: Hotter Benjamin , Hoffmann Sarah , Ulm Lena , Meisel Christian , Bustamante Alejandro , Montaner Joan , Katan Mira , Smith Craig J. , Meisel Andreas 
Published: December 2020

Background and Purpose:
Several clinical scoring systems as well as biomarkers have been proposed to predict stroke-associated pneumonia (SAP). We aimed to externally and competitively validate SAP scores and hypothesized that 5 selected biomarkers would improve performance of these scores.

Methods:
We pooled the clinical data of 2 acute stroke studies with identical data assessment: STRAWINSKI and PREDICT. Biomarkers (ultrasensitive procalcitonin; mid-regional proadrenomedullin; mid-regional proatrionatriuretic peptide; ultrasensitive copeptin; C-terminal proendothelin) were measured from hospital admission serum samples. A literature search was performed to identify SAP prediction scores. We then calculated multivariate regression models with the individual scores and the biomarkers. Areas under receiver operating characteristic curves were used to compare discrimination of these scores and models.

Results:
The combined cohort consisted of 683 cases, of which 573 had available backup samples to perform the biomarker analysis. Literature search identified 9 SAP prediction scores. Our data set enabled us to calculate 5 of these scores. The scores had area under receiver operating characteristic curve of 0.543 to 0.651 for physician determined SAP, 0.574 to 0.685 for probable and 0.689 to 0.811 for definite SAP according to Pneumonia in Stroke Consensus group criteria. Multivariate models of the scores with biomarkers improved virtually all predictions, but mostly in the range of an area under receiver operating characteristic curve delta of 0.05.

Conclusions:
All SAP prediction scores identified patients who would develop SAP with fair to strong capabilities, with better discrimination when stricter criteria for SAP diagnosis were applied. The selected biomarkers provided only limited added predictive value, currently not warranting addition of these markers to prediction models.

Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01264549 and NCT01079728.