bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recurrent solutions of the Lorenz system of differential equations
Authors: Zlatanovska Biljana , Dimovski Donc̆o 
Published: May 2022

By introducing new variables in the systems of difference equations from the paper [B. Zlatanovska and D. Dimovski, Systems of difference equations approximating the Lorentz system of differential equations, Contrib. Sec. Math. Tech. Sci. 33 (2012) 75–96], new systems of difference equations are obtained. The solutions of these new systems of difference equations depend only on the initial values [Formula: see text] and the coefficients [Formula: see text] . The power series whose coefficients are these solutions present the recurrent solutions for the Lorenz system of differential equations. A comparison between the behavior of the Lorenz system of differential equations and the local behavior of its recurrent solutions for small time steps is examined in examples by computer simulations, as in the papers [B. Zlatanovska and D. Dimovski, Systems of difference equations approximating the Lorentz system of differential equations, Contrib. Sec. Math. Tech. Sci. 33 (2012) 75–96; B. Zlatanovska and D. Dimovski, Systems of difference equations as a model for the Lorentz system, in Proc. Fifth Int. Scientific Conf. FMNS - 2013, Vol. I (Blagoevgrad, Bulgaria, 2013), pp. 102–107 and B. Zlatanovska, Approximation for the solutions of Lorenz system with systems of differential equations, Bull. Math. 41(1) (2017) 51–61].
Body Mass Index and Mammographic Density in a Multiracial and Multiethnic Population-Based Study
Authors: Barnard Mollie E. , Martheswaran Tarun , Van Meter Margaret , Buys Saundra S. , Curtin Karen , Doherty Jennifer Anne 
Published: May 2022

Abstract

Background:
Mammographic density (MD) is strongly associated with breast cancer risk. We examined whether body mass index (BMI) partially explains racial and ethnic variation in MD.

Methods:
We used multivariable Poisson regression to estimate associations between BMI and binary MD [Breast Imaging Reporting and Database System (BI-RADS) A&B versus BI-RADS C&D] among 160,804 women in the Utah mammography cohort. We estimated associations overall and within racial and ethnic subgroups and calculated population attributable risk percents (PAR%).

Results:
We observed the lowest BMI and highest MD among Asian women, the highest BMI among Native Hawaiian and Pacific Islander women, and the lowest MD among American Indian and Alaska Native (AIAN) and Black women. BMI was inversely associated with MD [RRBMI≥30 vs. BMI&lt;25 = 0.43; 95% confidence interval (CI), 0.42–0.44] in the full cohort, and estimates in all racial and ethnic subgroups were consistent with this strong inverse association. For women less than 45 years of age, although there was statistical evidence of heterogeneity in associations between BMI and MD by race and ethnicity (P = 0.009), magnitudes of association were similar across groups. PAR%s for BMI and MD among women less than 45 years were considerably higher in White women (PAR% = 29.2, 95% CI = 28.4–29.9) compared with all other groups with estimates ranging from PAR%Asain = 17.2%; 95% CI, 8.5 to 25.8 to PAR%Hispanic = 21.5%; 95% CI, 19.4 to 23.6. For women ≥55 years, PAR%s for BMI and MD were highest among AIAN women (PAR% = 37.5; 95% CI, 28.1–46.9).

Conclusions:
While we observed substantial differences in the distributions of BMI and MD by race and ethnicity, associations between BMI and MD were generally similar across groups.

Impact:
Distributions of BMI and MD may be important contributors to breast cancer disparities.
The Impact of Morbidity and Disability on Attendance at Organized Breast Cancer–Screening Programs: A Systematic Review and Meta-Analysis
Authors: McWilliams Lorna , Groves Samantha , Howell Sacha J. , French David P. 
Published: May 2022

Abstract
Individuals with morbidity experience worse breast cancer outcomes compared with those without. This meta-analysis assessed the impact of morbidity on breast cancer–screening attendance and subsequent early detection (PROSPERO pre-registration CRD42020204918). MEDLINE, PsychInfo, and CINAHL were searched. Included articles published from 1988 measured organized breast-screening mammography attendance using medical records by women with morbidity compared with those without. Morbidities were assigned to nine diagnostic clusters. Data were pooled using random-effects inverse meta-analyses to produce odds ratios (OR) for attendance. 25 study samples (28 articles) were included. Data were available from 17,755,075 individuals, including at least 1,408,246 participants with one or more conditions;16,250,556 had none. Individuals with any morbidity had lower odds of attending breast screening compared with controls [k = 25; OR, 0.76; 95% confidence interval (CI), 0.70–0.81; P = &lt;0.001; I2 = 99%]. Six morbidity clusters had lower odds of attendance. The lowest were for neurological, psychiatric, and disability conditions; ORs ranged from 0.45 to 0.59 compared with those without. Morbidity presents a clear barrier for breast-screening attendance, exacerbating health inequalities and, includes a larger number of conditions than previously identified. Consensus is required to determine a standardized approach on how best to identify those with morbidity and determine solutions for overcoming barriers to screening participation based on specific morbidity profiles.
SNPs atSMG7Associated with Time from Biochemical Recurrence to Prostate Cancer Death
Authors: Song Xiaoyu , Ru Meng , Steinsnyder Zoe , Tkachuk Kaitlyn , Kopp Ryan P. , Sullivan John , Gümüş Zeynep H. , Offit Kenneth , Joseph Vijai , Klein Robert J. 
Published: May 2022

AbstractBackground:A previous genome-wide association study identified several loci with genetic variants associated with prostate cancer survival time in two cohorts from Sweden. Whether these variants have an effect in other populations or if their effect is homogenous across the course of disease is unknown.Methods:These variants were genotyped in a cohort of 1,298 patients. Samples were linked with age, PSA level, Gleason score, cancer stage at surgery, and times from surgery to biochemical recurrence to death from prostate cancer. SNPs rs2702185 and rs73055188 were tested for association with prostate cancer–specific survival time using a multivariate Cox proportional hazard model. SNP rs2702185 was further tested for association with time to biochemical recurrence and time from biochemical recurrence to death with a multi-state model.Results:SNP rs2702185 at SMG7 was associated with prostate cancer–specific survival time, specifically the time from biochemical recurrence to prostate cancer death (HR, 2.5; 95% confidence interval, 1.4–4.5; P = 0.0014). Nine variants were in linkage disequilibrium (LD) with rs2702185; one, rs10737246, was found to be most likely to be functional based on LD patterns and overlap with open chromatin. Patterns of open chromatin and correlation with gene expression suggest that this SNP may affect expression of SMG7 in T cells.Conclusions:The SNP rs2702185 at the SMG7 locus is associated with time from biochemical recurrence to prostate cancer death, and its LD partner rs10737246 is predicted to be functional.Impact:These results suggest that future association studies of prostate cancer survival should consider various intervals over the course of disease.
All About That Ras: Novel Fusion Drives Ras Pathway Activation in Lung Cancer
Authors: Moorthi Sitapriya , Berger Alice H. 
Published: May 2022

Summary
Lung cancers in never- and light-smokers often harbor targetable oncogenic mutations in Ras pathway genes. Here, a novel OCLN-RASGRF1 fusion is identified in an otherwise Ras wild-type lung tumor. Studying this and other RASGRF1 fusions, the authors show that these fusions lead to malignant phenotypes that can be reversed by MEK inhibition.
See related article by Hunihan et al., p. 3091
Preclinical Evaluation of IMGC936, a Next-Generation Maytansinoid-based Antibody–drug Conjugate Targeting ADAM9-expressing Tumors
Authors: Scribner Juniper A. , Hicks Stuart W. , Sinkevicius Kerstin W. , Yoder Nicholas C. , Diedrich Gundo , Brown Jennifer G. , Lucas Jacquelynn , Fuller Megan E. , Son Thomas , Dastur Anahita , Hooley Jeff , Espelin Christopher , Themeles Marian , Chen Francine Z. , Li Ying , Chiechi Michael , Lee Jenny , Barat Bhaswati , Widjaja Lusiana , Gorlatov Sergey , Tamura James , Ciccarone Valentina , Ab Olga , McEachem Kerry A. , Koenig Scott , Westin Eric H. , Moore Paul A. , Chittenden Thomas , Gregory Richard J. , Bonvini Ezio , Loo Deryk 
Published: May 2022

Abstract
ADAM metallopeptidase domain 9 (ADAM9) is a member of the ADAM family of multifunctional, multidomain type 1 transmembrane proteins. ADAM9 is overexpressed in many cancers, including non–small cell lung, pancreatic, gastric, breast, ovarian, and colorectal cancer, but exhibits limited expression in normal tissues. A target-unbiased discovery platform based on intact tumor and progenitor cell immunizations, followed by an IHC screen, led to the identification of anti-ADAM9 antibodies with selective tumor-versus-normal tissue binding. Subsequent analysis revealed anti-ADAM9 antibodies were efficiently internalized and processed by tumor cells making ADAM9 an attractive target for antibody–drug conjugate (ADC) development. Here, we describe the preclinical evaluation of IMGC936, a novel ADC targeted against ADAM9. IMGC936 is comprised of a high-affinity humanized antibody site-specifically conjugated to DM21-C, a next-generation linker-payload that combines a maytansinoid microtubule-disrupting payload with a stable tripeptide linker, at a drug antibody ratio of approximately 2.0. In addition, the YTE mutation (M252Y/S254T/T256E) was introduced into the CH2 domain of the antibody Fc to maximize in vivo plasma half-life and exposure. IMGC936 exhibited cytotoxicity toward ADAM9-positive human tumor cell lines, as well as bystander killing, potent antitumor activity in human cell line-derived xenograft and patient-derived xenograft tumor models, and an acceptable safety profile in cynomolgus monkeys with favorable pharmacokinetic properties. Our preclinical data provide a strong scientific rationale for the further development of IMGC936 as a therapeutic candidate for the treatment of ADAM9-positive cancers. A first-in-human study of IMGC936 in patients with advanced solid tumors has been initiated (NCT04622774).
Increased Capillary Permeability in Heart Induces Diastolic Dysfunction Independently of Inflammation, Fibrosis, or Cardiomyocyte Dysfunction
Authors: Abelanet Alice , Camoin Marion , Rubin Sebastien , Bougaran Pauline , Delobel Valentin , Pernot Mathieu , Forfar Isabelle , Guilbeau-Frugier Céline , Galès Céline , Bats Marie Lise , Renault Marie-Ange , Dufourcq Pascale , Couffinhal Thierry , Duplàa Cécile 
Published: May 2022

Background:
While endothelial dysfunction is suggested to contribute to heart failure with preserved ejection fraction pathophysiology, understanding the importance of the endothelium alone, in the pathogenesis of diastolic abnormalities has not yet been fully elucidated. Here, we investigated the consequences of specific endothelial dysfunction on cardiac function, independently of any comorbidity or risk factor (diabetes or obesity) and their potential effect on cardiomyocyte.

Methods:

The ubiquitine ligase
Pdzrn3
, expressed in endothelial cells (ECs), was shown to destabilize tight junction. A genetic mouse model in which
Pdzrn3
is overexpressed in EC (iEC-Pdzrn3) in adults was developed.

Results:

EC-specific
Pdzrn3
expression increased cardiac leakage of IgG and fibrinogen blood-born molecules. The induced edema demonstrated features of diastolic dysfunction, with increased end-diastolic pressure, alteration of dP/dt min, increased natriuretic peptides, in addition to limited exercise capacity, without major signs of cardiac fibrosis and inflammation. Electron microscopic images showed edema with disrupted EC-cardiomyocyte interactions. RNA sequencing analysis of gene expression in cardiac EC demonstrated a decrease in genes coding for endothelial extracellular matrix proteins, which could be related to the fragile blood vessel phenotype. Irregularly shaped capillaries with hemorrhages were found in heart sections of iEC-
Pdzrn3
mice. We also found that a high-fat diet was not sufficient to provoke diastolic dysfunction; high-fat diet aggravated cardiac inflammation, associated with an altered cardiac metabolic signature in EC-
Pdzrn3
mice, reminiscent of heart failure with preserved ejection fraction features.

Conclusions:
An increase of endothelial permeability is responsible for mediating diastolic dysfunction pathophysiology and for aggravating detrimental effects of a high-fat diet on cardiac inflammation and metabolism.
Leu22_Leu23 Duplication at the Signal Peptide of PCSK9 Promotes Intracellular Degradation of LDLr and Autosomal Dominant Hypercholesterolemia
Authors: Benito-Vicente Asier , Uribe Kepa B. , Larrea-Sebal Asier , Palacios Lourdes , Cenarro Ana , Calle Xabier , Galicia-Garcia Unai , Jebari-Benslaiman Shifa , Sánchez-Hernández Rosa M. , Stef Marianne , Lambert Gilles , Civeira Fernando , Martín Cesar 
Published: May 2022

Background:
PCSK9 (Proprotein convertase subtilisin/kexin type 9) regulates LDL-C (low-density lipoprotein cholesterol) metabolism by targeting LDLr (LDL receptor) for lysosomal degradation. PCSK9 gain-of-function variants cause autosomal dominant hypercholesterolemia by reducing LDLr levels, the D374Y variant being the most severe, while loss-of-function variants are associated with low LDL-C levels. Gain-of-function and loss-of-function activities have also been attributed to variants occurring in the PCSK9 signal peptide. Among them, L11 is a very rare PCSK9 variant that seems to increase LDL-C values in a moderate way causing mild hypercholesterolemia.

Methods:
Using molecular biology and biophysics methodologies, activities of L8 and L11 variants, both located in the leucine repetition stretch of the signal peptide, have been extensively characterized in vitro.

Results:
L8 variant is not associated with increased LDLr activity, whereas L11 activity is increased by ≈20% compared with wt PCSK9. The results suggest that the L11 variant reduces LDLr levels intracellularly by a process resulting from impaired cleavage of the signal peptide. This would lead to less efficient LDLr transport to the cell membrane and promote LDLr intracellular degradation.

Conclusions:
Deletion of a leucine in the signal peptide in L8 variant does not affect PCSK9 activity, whereas the leucine duplication in the L11 variant enhances LDLr intracellular degradation. These findings highlight the importance of deep in vitro characterization of PCSK9 genetic variants to determine pathogenicity and improve clinical diagnosis and therapy of inherited familial hypercholesterolemia disease.
Aging Alters the Aortic Proteome in Health and Thoracic Aortic Aneurysm
Authors: Tyrrell Daniel J. , Chen Judy , Li Benjamin Y. , Wood Sherri C. , Rosebury-Smith Wendy , Remmer Henriette A. , Jiang Longtan , Zhang Min , Salmon Morgan , Ailawadi Gorav , Yang Bo , Goldstein Daniel R. 
Published: May 2022

Background:
Aging enhances most chronic diseases but its impact on human aortic tissue in health and in thoracic aortic aneurysms (TAA) remains unclear.

Methods:
We employed a human aortic biorepository of healthy specimens (n=17) and those that underwent surgical repair for TAA (n=20). First, we performed proteomics comparing aortas of healthy donors to aneurysmal specimens, in young (ie, <60 years of age) and old (ie, ≥60 years of age) subjects. Second, we measured proteins, via immunoblotting, involved in mitophagy (ie, Parkin) and also mitochondrial-induced inflammatory pathways, specifically TLR (toll-like receptor) 9, STING (stimulator of interferon genes), and IFN (interferon)-β.

Results:
Proteomics revealed that aging transformed the aorta both quantitatively and qualitatively from health to TAA. Whereas young aortas exhibited an enrichment of immunologic processes, older aortas exhibited an enrichment of metabolic processes. Immunoblotting revealed that the expression of Parkin directly correlated to subject age in health but inversely to subject age in TAA. In TAA, but not in health, phosphorylation of STING and the expression of IFN-β was impacted by aging regardless of whether subjects had bicuspid or tricuspid valves. In subjects with bicuspid valves and TAAs, TLR9 expression positively correlated with subject age. Interestingly, whereas phosphorylation of STING was inversely correlated with subject age, IFN-β positively correlated with subject age.

Conclusions:
Aging transforms the human aortic proteome from health to TAA, leading to a differential regulation of biological processes. Our results suggest that the development of therapies to mitigate vascular diseases including TAA may need to be modified depending on subject age.
Thrombectomy for Large‐Vessel Occlusion With Pretreatment Intracranial Hemorrhage
Authors: Tonetti Daniel A. , Desai Shashvat M. , Casillo Stephanie , Desai Sohum , Hassan Ameer E. , Flores‐Milan Gabriel , Mokin Maxim , Farooqui Mudassir , Ortega‐Gutierrez Santiago , Jadhav Ashutosh P. 
Published: May 2022

Background
Many patients treated with endovascular thrombectomy (EVT) in clinical practice would not have qualified for inclusion in the initial clinical trials demonstrating benefit for EVT, yet likely will benefit from reperfusion. One such subset for which data are sparse is patients with emergent large‐vessel occlusion and concomitant intracranial hemorrhage (ICH). The objective of this report is to document patients who underwent thrombectomy for large‐vessel occlusion in the presence of concomitant ICH and evaluate their clinical characteristics and outcomes.

Methods
We retrospectively reviewed prospectively collected patient records at 4 comprehensive stroke centers from 2012 to 2019. Patients were identified who had pre‐EVT ICH. Data collected included baseline patient demographics and laboratory values, stroke characteristics, ICH radiographic variables, antiplatelet/anticoagulant/thrombolytic medication use, and procedural factors. The primary safety outcome was any worsening of ICH on neuroimaging obtained 24 hours after EVT.

Results
Eight patients were identified who underwent thrombectomy with concomitant ICH. The mean age was 71.9 years (range, 37–90). Median National Institutes of Health Stroke Scale score was 25 (interquartile range, 16.5–28.8), and 5 (63%) received tissue plasminogen activator. All patients underwent EVT and had mTICI2B or greater reperfusion. In 7 patients (88%), the initial ICH remained stable on postprocedure imaging. In 1 patient who received intravenous antiplatelet agents during thrombectomy, the hemorrhagic transformation was radiographically increased but without clinical correlate or mass effect.

Conclusions
In a multi‐institution evaluation of 8 patients with ICH at the time of thrombectomy, 1 patient had radiographic worsening of hemorrhage, and no patient experienced clinical worsening related to hemorrhage progression. These findings suggest that thrombectomy may be safe in this population.
Influence of N-glycosylation in the A and C domains on the immunogenicity of factor VIII
Authors: Vander Kooi Amber , Wang Shuaishuai , Fan Meng-Ni , Chen Alex , Zhang Junping , Chen Chun-Yu , Cai Xiaohe , Konkle Barbara A. , Xiao Weidong , Li Lei , Miao Carol H. 
Published: May 2022

Abstract
The most significant complication in hemophilia A treatment is the formation of inhibitors against factor VIII (FVIII) protein. Glycans and glycan-binding proteins are central to a properly functioning immune system. This study focuses on whether glycosylation of FVIII plays an important role in induction and regulation of anti-FVIII immune responses. We investigated the potential roles of 4 N-glycosylation sites, including N41 and N239 in the A1 domain, N1810 in the A3 domain, and N2118 in the C1 domain of FVIII, in moderating its immunogenicity. Glycomics analysis of plasma-derived FVIII revealed that sites N41, N239, and N1810 contain mostly sialylated complex glycoforms, while high mannose glycans dominate at site N2118. A missense variant that substitutes asparagine (N) to glutamine (Q) was introduced to eliminate glycosylation on each of these sites. Following gene transfer of plasmids encoding B domain deleted FVIII (BDD-FVIII) and each of these 4 FVIII variants, it was found that specific activity of FVIII in plasma remained similar among all treatment groups. Slightly increased or comparable immune responses in N41Q, N239Q, and N1810Q FVIII variant plasmid-treated mice and significantly decreased immune responses in N2118Q FVIII plasmid-treated mice were observed when compared with BDD-FVIII plasmid-treated mice. The reduction of inhibitor response by N2118Q FVIII variant was also demonstrated in AAV-mediated gene transfer experiments. Furthermore, a specific glycopeptide epitope surrounding the N2118 glycosylation site was identified and characterized to activate T cells in an FVIII-specific proliferation assay. These results indicate that N-glycosylation of FVIII can have significant impact on its immunogenicity.
CD44–fibrinogen binding promotes bleeding in acute promyelocytic leukemia by in situ fibrin(ogen) deposition
Authors: Wang Chunxu , Wang Yufeng , Zuo Nan , Fang Shaohong , Shi Jialan 
Published: May 2022

AbstractEarly hemorrhagic death is still the main obstacle for the successful treatment of acute promyelocytic leukemia (APL). However, the mechanisms underlying hemostatic perturbations in APL have not been fully elucidated. Here, we report that CD44 on the membrane of APL blasts and NB4 cells ligated bound fibrinogen, resulting in in situ deposition of fibrin and abnormal fibrin distribution. Clots formed by leukemic cells in response to CD44 and fibrinogen interaction exhibited low permeability and resistance to fibrinolysis. Using flow cytometry and confocal microscopy, we found that CD44 was also involved in platelet and leukemic cell adhesion. CD44 bound activated platelets but not resting platelets through interaction with P-selectin. APL cell-coated fibrinogen-activated platelets directly induce enhanced procoagulant activity of platelets. In vivo studies revealed that CD44 knockdown shortened bleeding time, increased the level of fibrinogen, and elevated the number of platelets by approximately twofold in an APL mouse model. Moreover, CD44 expression on leukemic cells in an APL mouse model was not only associated with bleeding complications but was also related to the wound-healing process and the survival time of APL mice. Collectively, our results suggest that CD44 may be a potential intervention target for preventing bleeding complications in APL.