bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Unique Spectrum of Activating BRAF Alterations in Prostate Cancer
Authors: Chehrazi-Raffle Alex , Tukachinsky Hanna , Toye Eamon , Sivakumar Smruthy , Schrock Alexa B. , Bergom Hannah E. , Ebrahimi Hedyeh , Pal Sumanta , Dorff Tanya , Agarwal Neeraj , Mahal Brandon A. , Oxnard Geoffrey R. , Hwang Justin , Antonarakis Emmanuel S.
Published: October 2023

AbstractPurpose:
Alterations in BRAF have been reported in 3% to 5% of prostate cancer, although further characterization is lacking. Here, we describe the nature of BRAF alterations in prostate cancer using a large cohort from commercially available tissue and liquid biopsies subjected to comprehensive genomic profiling (CGP).
Experimental Design:
Tissue and liquid biopsies from patients with prostate cancer were profiled using FoundationOne CDx and FoundationOne Liquid CDx CGP assays, respectively. Tissue biopsies from non–prostate cancer types were used for comparison (n = 275,151). Genetic ancestry was predicted using a single-nucleotide polymorphism (SNP) based approach.
Results:
Among 15,864 tissue biopsies, BRAF-activating alterations were detected in 520 cases (3.3%). The majority (463 samples, 2.9%) harbored class II alterations, including BRAF rearrangements (243 samples, 1.5%), K601E (101 samples, 0.6%), and G469A (58 samples, 0.4%). BRAF-altered prostate cancers were enriched for CDK12 mutations (OR, 1.87; 9.2% vs. 5.2%; P = 0.018), but depleted in TMPRSS2 fusions (OR, 0.25; 11% vs. 32%; P < 0.0001), PTEN alterations (OR, 0.47; 17% vs. 31%; P < 0.0001), and APC alterations (OR, 0.48; 4.4% vs. 8.9%; P = 0.018) relative to BRAF wild-type (WT) disease. Compared with patients of European ancestry, BRAF alterations were more common in tumors from patients of African ancestry (5.1% vs. 2.9%, P < 0.0001) and Asian ancestry (6.0% vs. 2.9%, P < 0.001).
Conclusions:
Activating BRAF alterations were detected in approximately 3% of prostate cancers, and most were class II mutations and rearrangements; BRAF V600 mutations were exceedingly rare. These findings suggest that BRAF activation in prostate cancer is unique from other cancers and supports further clinical investigation of therapeutics targeting the mitogen-activated protein kinase (MAPK) pathway.
Data from Comprehensive Analysis of Tumor Microenvironment Reveals Prognostic ceRNA Network Related to Immune Infiltration in Sarcoma
Authors: Leng Dongliang , Yang Ziyi , Sun Heng , Song Chengcheng , Huang Chen , Ip Ka U. , Chen Guokai , Deng Chu-Xia , Zhang Xiaohua Douglas , Zhao Qi
Published: October 2023

AbstractPurpose:
Sarcoma is the second most common solid tumor type in children and adolescents. The high level of tumor heterogeneity as well as aggressive behavior of sarcomas brings serious difficulties to developing effective therapeutic strategies for clinical application. Therefore, it is of great importance to identify accurate biomarkers for early detection and prognostic prediction of sarcomas.
Experimental Design:
In this study, we characterized three subtypes of sarcomas based on tumor immune infiltration levels (TIIL), and constructed a prognosis-related competing endogenous RNA (ceRNA) network to investigate molecular regulations in the sarcoma tumor microenvironment (TME). We further built a subnetwork consisting of mRNAs and lncRNAs that are targets of key miRNAs and strongly correlated with each other in the ceRNA network. After validation using public data and experiments in vivo and in vitro, we deeply dug the biological role of the miRNAs and lncRNAs in a subnetwork and their impact on TME.
Results:
Altogether, 5 miRNAs (hsa-mir-125b-2, hsa-mir-135a-1, hsa-mir92a-2, hsa-mir-181a-2, and hsa-mir-214), 3 lncRNAs (LINC00641, LINC01146, and LINC00892), and 10 mRNAs (AGO2, CXCL10, CD86, CASP1, IKZF1, CD27, CD247, CD69, CCR2, and CSF2RB) in the subnetwork were identified as vital regulators to shape the TME. On the basis of the systematic network, we identified that trichostatin A, a pan-HDAC inhibitor, could potentially regulate the TME of sarcoma, thereby inhibiting the tumor growth.
Conclusions:
Our study identifies a ceRNA network as a promising biomarker for sarcoma. This system provides a more comprehensive understanding and a novel perspective of how ceRNAs are involved in shaping sarcoma TME.
Data from Safety and Tolerability of a Novel Anti-HER2 Antibody–Drug Conjugate (PF-06804103) in Patients with HER2-Expressing Solid Tumors: A Phase 1 Dose-Escalation Study
Authors: Meric-Bernstam Funda , Calvo Emiliano , Lee Keun Seok , Moreno Victor , Park Yeon Hee , Rha Sun Young , Chalasani Pavani , Zhong Wei , Zhou Li , Pirie-Shepherd Steven , Leung Abraham C.F. , Curigliano Giuseppe
Published: October 2023

Abstract
PF-06804103 is an anti-HER2 antibody–drug conjugate with auristatin payload. We evaluated its safety, tolerability, and antitumor activity in patients with advanced/unresectable or metastatic breast and gastric cancers. This multicenter, open-label, first-in-human, phase 1 study (NCT03284723) comprised dose escalation (P1) and dose expansion (P2). In P1, adults with HER2+ breast or gastric cancer received PF-06804103 0.15–5.0 mg/kg intravenously once/21 days (Q3W); in P2, patients with HER2+ or HER2-low (IHC 1+ or IHC 2+/ISH−) breast cancer received 3.0 or 4.0 mg/kg Q3W. The primary endpoints were dose-limiting toxicities (DLT) and safety (P1), and objective response rate (ORR) assessed using RECIST v1.1 (P2). Ninety-three patients enrolled in P1 (n = 47: HER2+ gastric cancer = 22, HER2+ breast cancer = 25) and P2 [n = 46: HER2+ breast cancer = 19, hormone receptor (HR)+ HER2-low breast cancer = 27] received PF-06804103. Four patients (3.0- and 4.0-mg/kg groups, n = 2 each) had DLTs (mostly Grade 3). Safety and efficacy results showed a dose–response relationship. Adverse events (AE) leading to treatment discontinuation (44/93, 47.3%) included neuropathy (11/93, 11.8%), skin toxicity (9/93, 9.7%), myalgia (5/93, 5.4%), keratitis (3/93, 3.2%), and arthralgia (2/93, 2.2%). Two (2/79, 2.5%) patients (P1, 4.0- and 5.0-mg/kg groups, n = 1 each) achieved complete response; 21 (21/79, 26.6%) achieved partial response. In P2, ORR was higher in HER2+ compared with HR+ HER2-low breast cancer [3.0 mg/kg: 16.7% (2/12) vs. 10.0% (1/10); 4.0 mg/kg: 47.4% (9/19) vs. 27.3% (3/11)]. PF-06804103 demonstrated antitumor activity; however, AEs led to discontinuation in 47.3% of patients. Safety and efficacy were dose-dependent.
Data from HCK Promotes High-Grade Serous Ovarian Cancer Tumorigenesis through CD44 and NOTCH3 Signaling
Authors: Khella Christen A. , Franciosa Lucyann , Rodirguez-Rodriguez Lorna , Rajkarnikar Resha , Mythreye Karthikeyan , Gatza Michael L.
Published: October 2023

Abstract
High-grade serous ovarian cancer (HGSOC) is a highly aggressive and lethal subtype of ovarian cancer. While most patients initially respond to standard-of-care treatment, the majority will eventually relapse and succumb to their disease. Despite significant advances in our understanding of this disease, the mechanisms that govern the distinctions between HGSOC with good and poor prognosis remain unclear. In this study, we implemented a proteogenomic approach to analyze gene expression, proteomic and phosphoproteomic profiles of HGSOC tumor samples to identify molecular pathways that distinguish HGSOC tumors relative to clinical outcome. Our analyses identify significant upregulation of hematopoietic cell kinase (HCK) expression and signaling in poor prognostic HGSOC patient samples. Analyses of independent gene expression datasets and IHC of patient samples confirmed increased HCK signaling in tumors relative to normal fallopian or ovarian samples and demonstrated aberrant expression in tumor epithelial cells. Consistent with the association between HCK expression and tumor aggressiveness in patient samples, in vitro phenotypic studies showed that HCK can, in part, promote cell proliferation, colony formation, and invasive capacity of cell lines. Mechanistically, HCK mediates these phenotypes, partly through CD44 and NOTCH3-dependent signaling, and inhibiting CD44 or NOTCH3 activity, either genetically or through gamma-secretase inhibitors, can revert HCK-driven phenotypes.
Implications:
Collectively, these studies establish that HCK acts as an oncogenic driver of HGSOC through aberrant activation of CD44 and NOTCH3 signaling and identifies this network as a potential therapeutic opportunity in a subset of patients with aggressive and recurrent HGSOC.
Data from Simultaneous Targeting of DNA Polymerase Theta and PARP1 or RAD52 Triggers Dual Synthetic Lethality in Homologous Recombination–Deficient Leukemia Cells
Authors: Sullivan-Reed Katherine , Toma Monika M. , Drzewiecka Malgorzata , Nieborowska-Skorska Margaret , Nejati Reza , Karami Adam , Wasik Mariusz A. , Sliwinski Tomasz , Skorski Tomasz
Published: October 2023

Abstract
DNA polymerase theta (Polθ, encoded by POLQ gene) plays an essential role in Polθ-mediated end-joining (TMEJ) of DNA double-strand breaks (DSB). Inhibition of Polθ is synthetic lethal in homologous recombination (HR)-deficient tumor cells. However, DSBs can be also repaired by PARP1 and RAD52-mediated mechanisms. Because leukemia cells accumulate spontaneous DSBs, we tested if simultaneous targeting of Polθ and PARP1 or RAD52 enhance the synthetic lethal effect in HR-deficient leukemia cells. Transformation potential of the oncogenes inducing BRCA1/2-deficiency (BCR-ABL1 and AML1-ETO) was severely limited in Polq−/−;Parp1−/− and Polq−/−;Rad52−/− cells when compared with single knockouts, which was associated with accumulation of DSBs. Small-molecule inhibitor of Polθ (Polθi) when combined with PARP or RAD52 inhibitors (PARPi, RAD52i) caused accumulation of DSBs and exerted increased effect against HR-deficient leukemia and myeloproliferative neoplasm cells.
Implications:
In conclusion, we show that PARPi or RAD52i might improve therapeutic effect of Polθi against HR-deficient leukemias.
Data from Allele-Specific Gene Regulation, Phenotypes, and Therapeutic Vulnerabilities in Estrogen Receptor Alpha–Mutant Endometrial Cancer
Authors: Blanchard Zannel , Rush Craig M. , Arnesen Spencer , Vahrenkamp Jeffery M. , Rodriguez Adriana C. , Jarboe Elke A. , Brown Callie , Chang Matthew E.K. , Flory Mark R. , Mohammed Hisham , Modzelewska Katarzyna , Lum David H. , Gertz Jason
Published: October 2023

Abstract
Activating estrogen receptor alpha (ER; also known as ESR1) mutations are present in primary endometrial and metastatic breast cancers, promoting estrogen-independent activation of the receptor. Functional characterizations in breast cancer have established unique molecular and phenotypic consequences of the receptor, yet the impact of ER mutations in endometrial cancer has not been fully explored. In this study, we used CRISPR-Cas9 to model the clinically prevalent ER-Y537S mutation and compared results with ER-D538G to discover allele-specific differences between ER mutations in endometrial cancer. We found that constitutive activity of mutant ER resulted in changes in the expression of thousands of genes, stemming from combined alterations to ER binding and chromatin accessibility. The unique gene expression programs resulted in ER-mutant cells developing increased cancer-associated phenotypes, including migration, invasion, anchorage-independent growth, and growth in vivo. To uncover potential treatment strategies, we identified ER-associated proteins via Rapid Immunoprecipitation and Mass Spectrometry of Endogenous Proteins and interrogated two candidates, CDK9 and NCOA3. Inhibition of these regulatory proteins resulted in decreased growth and migration, representing potential novel treatment strategies for ER-mutant endometrial cancer.
Implications:
This study provides insight into mutant ER activity in endometrial cancer and identifies potential therapies for women with ER-mutant endometrial cancer.
Data from PRIMARY PREVENTION AND INTERCEPTION STUDIES IN RAS-MUTATED TUMOR MODELS EMPLOYING SMALL MOLECULES OR VACCINES
Authors: Dragnev Konstantin H. , Lubet Ronald A. , Miller Mark Steven. , Sei Shizuko , Fox Jennifer T. , You Ming
Published: October 2023

Abstract
Therapeutic targeting of RAS-mutated cancers is difficult, whereas prevention or interception (treatment before or in the presence of preinvasive lesions) preclinically has proven easier. In the A/J mouse lung model, where different carcinogens induce tumors with different KRAS mutations, glucocorticoids and RXR agonists are effective agents in prevention and interception studies, irrespective of specific KRAS mutations. In rat azoxymethane-induced colon tumors (45% KRAS mutations), cyclooxygenase 1/2 inhibitors and difluoromethylornithine are effective in preventing or intercepting KRAS-mutated or wild-type tumors. In two KRAS mutant pancreatic models multiple COX 1/2 inhibitors are effective. Furthermore, combining a COX and an EGFR inhibitor prevented the development of virtually all pancreatic tumors in transgenic mice. In the N-nitroso-N-methylurea-induced ER positive rat breast model (50%HRAS mutations) various selective estrogen receptor modulators, aromatase inhibitors, epidermal growth factor receptor inhibitors, and retinoid X receptor agonists are profoundly effective in prevention and interception of tumors with wild type or mutant HRAS, while the farnesyltransferase inhibitor tipifarnib preferentially inhibits HRAS-mutant breast tumors. Thus, many agents not known to specifically inhibit the RAS pathway, are effective in an organ specific manner in preventing or intercepting RAS-mutated tumors. Finally, we discuss an alternative prevention and interception approach, employing vaccines to target KRAS.
Data from Analysis of Several Common APOBEC-type Mutations in Bladder Tumors Suggests Links to Viral Infection
Authors: Rao Nina , Starrett Gabriel J. , Piaskowski Mary L. , Butler Kelly E. , Golubeva Yelena , Yan Wusheng , Lawrence Scott M. , Dean Michael , Garcia-Closas Montserrat , Baris Dalsu , Johnson Alison , Schwenn Molly , Malats Nuria , Real Francisco X. , Kogevinas Manolis , Rothman Nathaniel , Silverman Debra T. , Dyrskjøt Lars , Buck Christopher B. , Koutros Stella , Prokunina-Olsson Ludmila
Published: October 2023

Abstract
FGFR3 and PIK3CA are among the most frequently mutated genes in bladder tumors. We hypothesized that recurrent mutations in these genes might be caused by common carcinogenic exposures such as smoking and other factors. We analyzed 2,816 bladder tumors with available data on FGFR3 and/or PIK3CA mutations, focusing on the most recurrent mutations detected in ≥10% of tumors. Compared to tumors with other FGFR3/PIK3CA mutations, FGFR3-Y375C was more common in tumors from smokers than never-smokers (P = 0.009), while several APOBEC-type driver mutations were enriched in never-smokers: FGFR3-S249C (P = 0.013) and PIK3CA-E542K/PIK3CA-E545K (P = 0.009). To explore possible causes of these APOBEC-type mutations, we analyzed RNA sequencing (RNA-seq) data from 798 bladder tumors and detected several viruses, with BK polyomavirus (BKPyV) being the most common. We then performed IHC staining for polyomavirus (PyV) Large T-antigen (LTAg) in an independent set of 211 bladder tumors. Overall, by RNA-seq or IHC-LTAg, we detected PyV in 26 out of 1,010 bladder tumors with significantly higher detection (P = 4.4 × 10−5), 25 of 554 (4.5%) in non–muscle-invasive bladder cancers (NMIBC) versus 1 of 456 (0.2%) of muscle-invasive bladder cancers (MIBC). In the NMIBC subset, the FGFR3/PIK3CA APOBEC-type driver mutations were detected in 94.7% (18/19) of PyV-positive versus 68.3% (259/379) of PyV-negative tumors (P = 0.011). BKPyV tumor positivity in the NMIBC subset with FGFR3- or PIK3CA-mutated tumors was also associated with a higher risk of progression to MIBC (P = 0.019). In conclusion, our results support smoking and BKPyV infection as risk factors contributing to bladder tumorigenesis in the general patient population through distinct molecular mechanisms.
Prevention Relevance:
Tobacco smoking likely causes one of the most common mutations in bladder tumors (FGFR3-Y375C), while viral infections might contribute to three others (FGFR3-S249C, PIK3CA-E542K, and PIK3CA-E545K). Understanding the causes of these mutations may lead to new prevention and treatment strategies, such as viral screening and vaccination.
Extensive, 3.8 Mb-Sized Deletion of 22q12 in a Patient with Bilateral Schwannoma, Intellectual Disability, Sensorineural Hearing Loss, and Epilepsy
Authors: Trizuljak Jakub , Duben Jakub , Blaháková Ivona , Vrzalová Zuzana , Kozubík Kateřina Staňo , Štika Jiří , Radová Lenka , Bergerová Veronika , Mejstříková Soňa , Hořínová Věra , Jancalek Radim , Pospíšilová Šárka , Doubek Michael
Published: October 2023

Introduction: In contrast with the well-known and described deletion of the 22q11 chromosome region responsible for DiGeorge syndrome, 22q12 deletions are much rarer. Only a few dozen cases have been reported so far. This region contains genes responsible for cell cycle control, chromatin modification, transmembrane signaling, cell adhesion, and neural development, as well as several cancer predisposition genes. Case Presentation: We present a patient with cleft palate, sensorineural hearing loss, vestibular dysfunction, epilepsy, mild to moderate intellectual disability, divergent strabism, pes equinovarus, platyspondylia, and bilateral schwannoma. Using Microarray-based Comparative Genomic Hybridization (aCGH), we identified the de novo 3.8 Mb interstitial deletion at 22q12.1→22q12.3. We confirmed deletion of the critical NF2 region by MLPA analysis. Discussion: Large 22q12 deletion in the proband encases the critical NF2 region, responsible for development of bilateral schwannoma. We compared the phenotype of the patient with previously reported cases. Interestingly, our patient developed cleft palate even without deletion of the MN1 gene, deemed responsible in previous studies. We also strongly suspect the DEPDC5 gene deletion to be responsible for seizures, consistent with previously reported cases.
Novel SYNGAP1 Variant in an Adult Individual Affected by Intellectual Disability and Epilepsy: A Cold Case Solved through Whole-Exome Sequencing
Authors: Rosti Giulia , Boeri Silvia , Divizia Maria Teresa , Pisciotta Livia , Mancardi Maria Margherita , Lerone Margherita , Cerminara Maria , Servetti Martina , Spirito Giovanni , Vozzi Diego , Fontana Marco , Gustincich Stefano , Nobili Lino , Zara Federico , Puliti Aldamaria
Published: October 2023

Introduction: Nowadays, whole-exome sequencing (WES) analysis is an essential part in the diagnostic pathway of individuals with complex phenotypes when routine exams, such as array-CGH and gene panels, have proved inconclusive. However, data on the diagnostic rate of WES analysis in adult individuals, negative to first-tier tests, are lacking. This is because initiatives with the aim of diagnosing rare diseases focus mainly on pediatric unsolved cases. Case Presentation: We hereby present a 45-year-old woman with severe intellectual disability, previous psychomotor developmental delay, behavioral disorders, stereotypies, nonconvulsive epilepsy, and dysmorphisms. The proband first came to our attention when she was 4 years old (in 1982); since then, she has undergone several clinical and instrumental assessments, without reaching a genetic diagnosis. At last, through WES analysis, a novel de novo variant in SYNGAP1 was found. The clinical characteristics associated with SYNGAP1 are similar to those presented by the proband. Conclusion: The variant is predicted to be deleterious and is most probably the cause of the proband’s phenotype. The perseverance of the clinicians and the family allowed us to reach a diagnosis in a woman with a more than 30-year history of clinical evaluations, instrumental assessments, and genetic tests. This diagnosis was of significant relevance in genetic counseling for family members and the proband herself.
Essay: Linking Keynesian Theory to Economic Geography
Authors: Ahn Young-Jin , Juraev Zuhriddin
Published: October 2023

This article examines the application of Keynesian theory in the field of economic geography, with a specific focus on regional development and the reduction of inequalities. The objective is to emphasize the importance and advantages of applying Keynesian principles to address spatial economic challenges. The novelty lies in examining the intersection of Keynesian economics and geography, which provides insights into regional planning, infrastructure development, and cluster formation. The results demonstrate how policymakers and researchers can utilize Keynesian theory to foster balanced growth and enhance living standards. The keywords for this article are Keynesian theory, economic geography, regional development, disparities, and policy interventions.
The Interrelationship between Human Resource Roles and Human Resource Management Effectiveness: Empirical Evidence from a Developing Country
Authors: Shakil Rashed Mahmud , Karim Md. Arfanul , Uddin Mohammad Jidhan , Chowdhury Titon
Published: October 2023

The issue of effective human resource (HR) roles performance and the effectiveness of HR operations at Bangladeshi private banking sector has grown in importance over the past few decades. The scholarly literature, however, largely lacks the empirical research examining the impact of four HR roles on HRM effectiveness. The prime objective of the current research includes testing the causal relationships between four HR roles (employee champion, strategic partner, change agent, and administrative expert) and HRM effectiveness. Data was gathered from the first-line managers employed in the private commercial banks in Bangladesh (n = 210). The hypothesized model was examined utilizing partial least squares structural equation modelling, or PLS-SEM. The findings showed that the roles of employee champion, strategic partner, change agent, and administrative expert had a positive and significant impact on HRM effectiveness. The implications regarding the findings are explained and recommendations for further research are also proposed.
Online teaching experiences during a global crisis: Private school teachers’ narratives in the Emirates
Authors: Lemana II Henry E. , Torres John Rey L. , Cabiling Karla Jane P. , Ahmad Crizjale V.
Published: October 2023

The educational sector, like many other aspects of human life worldwide, has faced unparalleled challenges due to the COVID-19 pandemic. This study investigated the perspectives of conveniently selected secondary school teachers at a private school in the United Arab Emirates regarding the transition from in-person to online teaching, aiming to enhance the effectiveness of online learning. Employing a qualitative-descriptive design, the study generated findings that revealed that utilizing diverse teaching strategies and creating interactive online learning environments promoted student engagement. Moreover, teachers established a friendly and secure online classroom where students were encouraged to actively participate and share their thoughts on the subject matter. However, several challenges were identified, including technological difficulties, low student engagement, academic dishonesty, and feelings of isolation resulting from a lack of peer interaction, all of which significantly impacted the well-being of the participants. Despite these obstacles, teachers remained committed to their profession and maintained a passion for supporting their families. The study recommends encouraging teachers to continue integrating technology into the teaching and learning process, embracing innovative methodologies, and providing logistical and psychological support to effectively navigate the challenges posed by educational disruptions. Findings also provide a significant backdrop for the improvement of the implementation and effectiveness of digital education.
The Effect of Pictures in Writing Narrative Text of Students of Junior High
Authors: Siahaan Mungkap Mangapul , Sinaga Asima Rohani , Sirait Jumaria , Sibarani Ega Putri Sani , Pasaribu Sunggul
Published: October 2023

This study aims to investigate whether or not there is an effect of Picture Teaching Model in teaching narrative text for the ninth grades students of SMPN 2 Pematangsiantar. The method used in the research is a true experimental design method. In the method, the researcher used two classes as one control class and one experimental class. The experimental class was taught with a treatment as Picture Teaching Model and the control class was taught with a conventional model. The sampling was selected by random sampling, as class 〖IX〗^5 as control class consisted of 32 students and class 〖IX〗^7 as experimental class consists of 32 students. The means of experimental group was higher that that the control group (20.75 – 14.53 = 2.87), the two means of both experimental and control group was different. If this difference can show that t-test is greater than t-table, that it is significant. The value of t-test has higher than t-table 6.98>2.00. It means that there is a significances after Picture Teaching Model is used to teach writing narrative text. Based on calculation of t-test is (6.98) is higher than t-table at the level of significance (2.00). If the result of t-test is higher than t-table (6.98>2.00), the null hypothesis (H0) is rejected and alternative hypothesis (Ha) is accepted. The results state that there is an influence of Picture Teaching Model in Narrative text learning in class IX of SMPN 2 Pematangsiantar.
Assessing the Influence of Source Characteristics, Psychological-Related Factors, and Content Attributes on Purchase Intention: The Case of an International Cosmetics Company in the Philippines
Authors: Tanpoco Manuel R. , Alonte Alexis Therese L. , Nubla Candace Anne D. , De Arellano Dominique Marie B. Ramirez , Torres Ralph Phillip F. , Caminong Joliber M. , Morales Retchell Rubin L.
Published: October 2023

Influencer Marketing has become a widely used strategy wherein social media influencers partner with businesses to create awareness about their brand and promote their products. XYZ (not real name) Cosmetics, an international cosmetics company that provides affordable, high-quality products to the Philippine market, is one such company that embraces the trend. It has integrated influencer marketing to better connect with its customers. This study determines the relationship between the three aspects of influencers: Source Characteristics (Attractiveness and Popularity), Psychological-Related Influential Factors (Self-Congruency and Product Match-Up), and Content Attributes (Quality and Uniqueness) with XYZ's Customer Purchase Intention (CPI). Through using a case study survey research design, the study chose 387 respondents, randomly sampling the Instagram followers of XYZ. An online questionnaire consisting of seven-point Likert scale items was administered. The results show that Attractiveness, Uniqueness, and Self-Congruency significantly affect customer purchase intention, while Popularity, Product Match-up, and Quality do not. The study has implications for brand managers and entrepreneurs, underscoring how an influencer should be selected, especially for cosmetics companies like XYZ. The researchers recommend choosing an attractive and unique influencer known to possess credibility, an amiable personality, and good values while focusing less on assessing how well the influencer vlogs, how popular the talent is, and how matched the person is with the company's products.
Abstract 659: Plasminogen Activator Inhibitor-1 (PAI-1) Increases Mitochondrial Membrane Potential In Vascular Smooth Muscle Cells And Coronary Arteries
Authors: Schoenherr Alex , Norton Charles , Vadali Manisha , Bryson Alaina , Fay William P , Ji Yan
Published: October 2023

Background:
Plasminogen activator inhibitor- 1 (PAI-1) expression is increased in cardiometabolic diseases associated with mitochondrial dysfunction and atherosclerosis, including obesity and diabetes mellitus. However, the role of PAI-1 in triggering mitochondrial dysfunction in the vasculature is poorly defined. Mitochondrial membrane potential (ΔΨm) is as a central bioenergetic parameter controlling reactive oxygen species (ROS) generation. We investigated the roles of PAI-1 in controlling Ψm in human coronary artery smooth muscle cells (HCASMCs) and murine coronary arteries, as well as ROS production in the arterial wall.

Methods:
HCASMCs were cultured in high glucose (25 mM), normal glucose (4.6 mM), and isosmotic control (mannitol 25 mM) conditions (with and without PAI-039, a specific PAI-1 inhibitor) for 1 hour. JC-1 (5 μM), a ratiometric marker of mitochondrial membrane potential, was added and red/green fluorescent imaging was used to quantify ΔΨm. To evaluate effects of PAI-1 on ΔΨm and mitochondrial ROS production in the vessel wall, coronary artery segments were isolated from wild-type (WT) and PAI-1-deficient mice, pressurized
ex vivo
(100 cmH
2
O), loaded with JC-1 (5μM) and Mitosox (5 μM), then subjected to quantitative fluorescence imaging.

Results:
Compared to vehicle control, PAI-039 significantly decreased ΔΨm in HCASMCs under all experimental conditions (normal glucose: 2.08±0.15
vs
. 1.47±0.04 AU; high glucose: 2.49±0.05
vs
. 1.83±0.15 AU; and isosmotic control: 2.04±0.09
vs
. 1.52±0.07 AU, n=4 for all groups, P<0.05 for all comparisons). The ΔΨm was significantly lower in coronary arteries from PAI-1-deficient mice vs. WT controls (0.85±0.03
vs
. 1.09±0.09AU, n=6/group, P<0.05). Coronary arteries from PAI-1 knockout mice showed a statistically insignificant trend toward decreased ROS production
vs
. WT controls (6.4± 1.44
vs
. 10.2±1.31 AU, n=6/group, P=0.07).

Conclusion:
Pharmacologic inhibition of PAI-1 decreases ΔΨm in HCASMCs. Endogenous expression of PAI-1 increases ΔΨm in coronary arteries, which is accompanied by a trend towards increased ROS production. These findings indicate that PAI-1 regulates mitochondrial function in vascular SMCs and by such effects may increase ROS generation in the vasculature.
Abstract 674: Transgelin Deficiency Is Associated With Elevated Low-density Lipoprotein Cholesterol And Atherogenesis In Mice.
Authors: Lucero Diego , Aligabi Zahra , Pryor Milton , Yang Zhi-Hong , Kun Julia , Rojulpote Vamsi , Sviridov Denis O , YU Zu-Xi , Remaley Alan
Published: October 2023

Genetic hyperlipidemias are a major risk factor for atherosclerotic cardiovascular disease due to life-long exposure to elevated plasma lipids. However, the causality of hyperlipidemia is not known in a large proportion of patients, suggesting that unknown genes remain to be discovered. Applying a CRISPR/Cas9 screen, we recently identified transgelin (TAGLN), an actin binding protein, as a new gene involved in LDL metabolism. TAGLN supports LDL endocytosis presumably by interacting with actin filaments during LDL endocytosis; however, if TAGLN impacts on plasma lipid levels and atherogenesis
in vivo
is unknown.

Aim:
To investigate TAGLN’s impact on lipid profile and atherosclerosis development in a
Tagln
-knockout (KO) mouse model.

Methods:
Tagln
-KO (n=18) and wild-type (WT) (n=18) mice were fed a high-fat diet (42% Cal from fat) for 12 weeks. We collected plasma for lipoprotein analysis, liver specimens for histopathology and lipid extraction/quantification, and aortas for quantifying atherosclerotic plaque area.

Results:
Tagln
-KO mice showed higher total cholesterol than WT mice (20% increase, mean±SD: 299±51 vs. 251±59 mg/dL, p=0.014), without changes in triglyceride levels (p=0.36). Lipoprotein subfraction analysis by FPLC revealed an increase in the lipids associated with the LDL fraction of
Tagln
-KO mice. Although no differences were observed in hepatic histology or triglyceride content,
Tagln
-KO animals showed an increase in the hepatic content of total cholesterol (mean±SD: 376±65 vs. 317±70 μg/100 mg, p=0.012). Finally,
Tagln
-KO mice developed about twice more atherosclerotic lesion area than WT mice (Median(IQR): 0.997(0.347-1.451) vs 0.428(0.336-0.859), p=0.015).

Conclusions:
In line with a reduction in LDL uptake in hepatocytes, shown by our previous
in vitro
data, TAGLN deficiency was associated with hypercholesterolemia and high LDL cholesterol in mice, likely due to decreased hepatic LDL clearance. Despite the modest hypercholesterolemia,
Tagln
-KO mice showed disproportionally increased atherosclerosis, suggesting that TAGLN may regulate other atherogenic mechanisms, beyond LDL cholesterol.
Abstract 679: HDL Apolipoproteomic Score, Cardiometabolic Risk, And Exercise Training
Authors: Miranda Maravi Juan S , Schwartz Charles S , Dev Prasun K , Barber Jacob L , Reasons Riley J , Pearce Ryan W , Mcphaul Michael J , Gerszten Robert E , Rohatgi Anand , Bouchard Claude , Collier Timothy S , Sarzynski Mark A
Published: October 2023

Background:
Previous studies have derived and validated an HDL apolipoproteomic score (pCAD) that predicts coronary artery disease risk. However, the relationship between pCAD and the cardiometabolic profile in healthy adults, as well as the effects of regular exercise on pCAD are unknown.

Methods:
A total of 642 inactive but healthy adults (56% female, 36% Black, 35±13 yrs) completed 20 weeks of endurance exercise training. HDL-bound proteins were measured in APOA1-tagged serum using targeted LC-MS/MS (Quest Diagnostics). The pCAD index was calculated as a weighted sum of five HDL-associated apolipoproteins (APO A1, C1, C2, C3, C4) with scores from 0 to 100 (higher score=higher risk). Age-, sex-, and race-specific baseline pCAD quartiles were created.

Results:
The mean (SD) pCAD score at baseline was 29 (32). At baseline, increasing pCAD quartile was associated with a poorer cardiometabolic profile, including higher total and visceral fat, blood pressure, inflammation, and fasting glucose and lower insulin sensitivity and lipoprotein lipase activity (
Table
). In the total sample, pCAD significantly decreased with exercise training by 4.7 (25) pts or ~16%. Across pCAD quartiles, mean decreases in pCAD were 4.6 in quartile 3 and 21.3 in quartile 4, compared to mean increases of 3.6 in quartile 1 and 3.5 in quartile 2 (p<0.05 for all within group changes). The exercise-induced decrease in pCAD was largely driven by increases in HDL-associated APOA1 and APOC1 levels and inversely correlated with changes in HDL-C (r= -0.17, p<0.0001) and HDL size (r= -0.14, p=0.0006). Otherwise, changes in pCAD were not correlated with changes in other cardiometabolic traits.

Conclusions:
A higher pCAD index was associated with a poor cardiometabolic profile at baseline and improved with regular exercise in healthy adults with the worst profiles. These findings highlight the potential role of HDL apolipoproteins as a theranostic target for lifestyle interventions in these individuals.
Abstract 713: Pharmacovigilance Analysis Of FDA Adverse Event Reporting System (FAERS) Events For Inclisiran
Authors: Rajak Kripa , Halder Anupam , Sharma Gautam Seema , Khanal Resha , Atrash Anas , Goswami Rohan
Published: October 2023

Background:
Inclisiran is a first-in-class, cholesterol-lowering small interfering RNA based therapy for treatment of atherosclerosis or familial hypercholesterolemia as an adjunct to maximally tolerated statin therapy. Since approval by FDA in December 2021, it is getting increasingly popular due to biannual regimen. During trials and upon review for FDA approval, it exhibited injection site reaction, arthralgia, urinary tract infection, diarrhea, and dyspnea.

Objective:
In view of increased usage, it is important to establish a side effect profile of inclisiran in general population since the ORION 9, 10 and 11 trials.

Methods:
We explored reported adverse events (AEs) of inclisiran using FDA Adverse Event Reporting System (FAERS). A total of 472 AEs were reported until September 2022. 44.49% AEs were reported by healthcare professionals (HCPs), which were further analyzed. AEs were analyzed in men (35.2%) vs women (45.2%) and in three age groups of 18-64, 65-85, and >85 years.

Results:
A total of 100 (47%) events were serious including 38% hospitalization and 14% deaths. The most frequently reported AE was surprisingly dyspnea in conjunction with cough (21.9%) followed by myalgia (15.2%), injection site pain (5.2%), arthralgia (4.3%), diarrhea (4.3%), rash (3.3%) and fatigue (2.4%). Most AEs were consistent with ORION trial except elevated LDL (8.2%), acute myocardial infarction (AMI) (7.6%), hyponatremia (6.6%), acute kidney injury (AKI) (3.3%) and headache (2.4%). It was reported more in women of age group 65-85 years.

Discussion:
The events of death and hospitalization after initiating inclisiran could have been associated with AMI, AKI and hyponatremia that are newly reported since the trial, however the temporality and mechanisms are unknown. Even though the trial has shown that this drug is relatively safe, physicians must be vigilant about the new developments to avoid decompensation in vulnerable patients. Its use in patients with pulmonary disease can worsen dyspnea.

Conclusion:
With the current increasing use of inclisiran, there is a need for more data on safety profile. In future, further randomized trials are required to better assess the safety profile focusing on temporality and mechanisms of AMI and AKI in relation to inclisiran.
Abstract 716: Elabela Ameliorates Atherogenesis Through Restoring The M1/M2 Macrophage Balance In Apoe
-/-
Mice
Authors: Xu Chuanming , Le Tang , Yi Xiaoli
Published: October 2023

Atherosclerosis is the leading cause of death in patients with cardiovascular disease worldwide. ELABELA, an early endogenous ligand for the G protein-coupled receptor APJ (apelin peptide jejunum, apelin receptor), maybe a novel therapeutic target for multiple cardiovascular diseases. The major goal of the present study was to test the potential therapeutic action of ELABELA in atherogenesis and the underlying mechanisms. ELABELA-21 (ELA-21) was used to treat low-density lipoprotein (ox-LDL)-incubated macrophages to detect macrophage foaminess. ApoE
-/-
mice were fed a high-fat diet (HFD) for 16 weeks and received subcutaneous injections of ELA-21 peptides (1 mg/kg/day) in the last 4 weeks to detect atherosclerotic plaque area, macrophage infiltration, and the balance between M1 and M2 macrophages. ELA-21 significantly ameliorated atherosclerosis in HFD-fed ApoE
-/-
mice, as characterized by significantly decreased atherosclerotic plaque area (40%, assessed by Oil-red-O staining), inhibited macrophage infiltration (45%, assessed by CD68 staining), and increased collagen content (65%, assessed by α-SMA staining). By RT-qPCR, ELA-21 treatment inhibited the mRNA expression of
Icam-1
(49%),
iNOS
(53%),
IL-1β
(59%),
IL-6
(55%), and
Mc
p-1
(80%) in the aorta of HFD-fed ApoE
-/-
mice.
In vitro
, ELA-21 treatment inhibited macrophage-derived foam cell formation (75.5%) induced by ox-LDL assessed by Oil-red-O staining. Additionally, in macrophages from the abdominal cavity of HFD-fed ApoE
-/-
mice, ELA-21 treatment abolished the lipid accumulation (50%) assessed by Oil-red-O staining, and modulated the balance between M1 and M2 macrophages toward a more anti-inflammatory status in HFD-fed ApoE
-/-
mice, as characterized by the significantly decreased mRNA levels of
IL-1β
(94%),
Tnf-α
(55%),
iNOS
(99%), and
IL-12β
(99%) (the markers of M1 macrophages), and elevated mRNA expression of
Fizz1
(17777%),
IL-10
(529%), and
Cd206
(24%)(the markers of M2 macrophages). Collectively, our data highlighted an anti-atherosclerotic effect of ELA-21 by restoring the M1/M2 macrophage balance.
Abstract 723: Positional Transcriptomics Defines Regionally Restricted Sex-specific Differences Of The Vessel Wall
Authors: Romay Milagros , Ma Feiyang , Hernandez Gloria E , Mompeon Campos Ana , Salvador Jocelynda , Kimball Todd H , Pellegrini Matteo , Iruela Arispe Luisa I
Published: October 2023

Cardiovascular diseases (CVDs) remain the leading causes of morbidity and mortality for both men and women, globally. Abdominal aortic aneurysm (AAA) represents a class of CVD with significant sex-stratification as disease burden is higher in males, but outcome of disease is poorer in females. Establishment of AAA is a complex process, defined by the interaction of multiple environmental influences and host regional vascular heterogeneity. While is it is known that many factors including developmental origin, local cellular diversity and regional bio-mechanical forces contribute to vascular bed specialization, the exact contribution of biological sex in vascular heterogeneity remains unknown. To elucidate the molecular contribution of sex to vascular heterogeneity of large arterial beds we performed single cell sequencing from cells isolated from 4 distinct anatomic locations of both male and female young adult mice: the carotid arteries, aortic arch, thoracic and abdominal aorta. Using this approach, we identified anatomic sex-invariant gene signatures as well as regional sex-specific gene signatures in vascular smooth muscle cells (vSMC) and used immunohistochemistry to validate these findings. Surprisingly, prominent regional-sex dependent differences were observed in vSMCs of the thoracic and abdominal aorta, consistent with sex-specific burden of aneurysm in these regions. From these sex-specific regionally restricted vSMC signatures, we identified several enriched signature genes that are likely contributors in the regulation of AAA development in mice and humans.
Automated motion artifact detection in early pediatric diffusion MRI using a convolutional neural network
Authors: Weaver Jayse Merle , DiPiero Marissa , Rodrigues Patrik Goncalves , Cordash Hassan , Davidson Richard J. , Planalp Elizabeth M. , Dean III Douglas C.
Published: October 2023

Diffusion MRI (dMRI) is a widely used method to investigate the microstructure of the brain. Quality control (QC) of dMRI data is an important processing step that is performed prior to analysis using models such as diffusion tensor imaging (DTI) or neurite orientation dispersion and density imaging (NODDI). When processing dMRI data from infants and young children, where intra-scan motion is common, the identification and removal of motion artifacts is of the utmost importance. Manual QC of dMRI data is (1) time-consuming due to the large number of diffusion directions, (2) expensive, and (3) prone to subjective errors and observer variability. Prior techniques for automated dMRI QC have mostly been limited to adults or school-age children. Here, we propose a deep learning-based motion artifact detection tool for dMRI data acquired from infants and toddlers. The proposed framework uses a simple three-dimensional convolutional neural network (3DCNN) trained and tested on an early pediatric dataset of 2,276 dMRI volumes from 121 exams acquired at 1 month and 24 months of age. An average classification accuracy of 95% was achieved following four-fold cross-validation. A second dataset with different acquisition parameters and ages ranging from 2-36 months (consisting of 2,349 dMRI volumes from 26 exams) was used to test network generalizability, achieving 98% classification accuracy. Finally, to demonstrate the importance of motion artifact volume removal in a dMRI processing pipeline, the dMRI data were fit to the DTI and NODDI models and the parameter maps were compared with and without motion artifact removal.
A meso-scale cartography of the AI ecosystem
Authors: Gargiulo Floriana , Fontaine Sylvain , Dubois Michel , Tubaro Paola
Published: October 2023

Recently, the set of knowledge referred to as “artificial intelligence” (AI) has become a mainstay of scientific research. AI techniques have not only greatly developed within their native areas of development but have also spread in terms of their application to multiple areas of science and technology. We conduct a large-scale analysis of AI in science. The first question we address is the composition of what is commonly labeled AI, and how the various subfields within this domain are linked together. We reconstruct the internal structure of the AI ecosystem through the co-occurrence of AI terms in publications, and we distinguish between 15 different specialties of AI. Furthermore, we investigate the spreading of AI outside its native disciplines. We bring to light the dynamics of the diffusion of AI in the scientific ecosystem and we describe the disciplinary landscape of AI applications. Finally we analyze the role of collaborations for the interdisciplinary spreading of AI. Although the study of science frequently emphasizes the openness of scientific communities, we show that collaborations between those scholars who primarily develop AI and those who apply it are quite rare. Only a small group of researchers can gradually establish bridges between these communities.
On Veronica paczoskiana and the real identity and typification of V. spicata var. pseudoorchidea (Plantaginaceae)
Authors: MOSYAKIN SERGEI L. , ALBACH DIRK C. , SHEVERA MYROSLAV V.
Published: October 2023

Our critical re-assessment of the relevant publications by Paczoski and other available literature demonstrated that the name Veronica spicata var. pseudoorchidea was validly published, with a rather detailed descriptive statement and discussion, not in 1910 (in that Paczoski’s book, this variety was briefly discussed but not named) and not from southern Ukraine (as it was suggested by Klokov in 1976, and in several publications by other authors), but in 1909 in Paczoski’s article on the flora and vegetation of the area near the Motovylivka railway station, now in Fastiv District of Kyiv Region, located at the border of the northern Forest Zone (Polissya, Polesie) and the Forest-Steppe Zone of Ukraine. In that article Paczoski, in particular, mentioned that his plant specimens collected in that area are deposited in the herbarium of the Kherson Regional Museum (Kherson, Ukraine). The study of two original specimens of V. spicata var. pseudoorchidea (syntypes, of which one is here designated as the lectotype) in the herbarium of Paczoski held at the Museum clearly demonstrated that the morphological characters of these plants perfectly correspond to the characters indicated by Klokov for his supposedly distinct taxon, V. paczoskiana (described from the Mykhaylivka Forest near Kaniv, Cherkasy Region, Ukraine), and the syntypes of V. spicata var. pseudoorchidea do not differ from the holotype and other original specimens of V. paczoskiana at KW. Thus, if accepted as a variety, the glabrous or sparsely pubescent plants growing mainly in pine forests of Ukraine, Belarus, partly also in the European part of Russia and Siberia should be called V. spicata var. pseudoorchidea. If such plants were accepted at a species or subspecies rank, their correct names would be V. paczoskiana or V. spicata subsp. paczoskiana, respectively. Based on analyses of DNA polymorphisms and morphological data (analyzed separately), we prefer the rank of variety.
Description of a new species of the genus Mallomonas from section Mallomonas (Synurales, Chrysophyceae) in the tropics
Authors: GUSEV EVGENIY , MARTYNENKO NIKITA , SHKURINA NATALIYA , DIEN TRAN DUC
Published: October 2023

Mallomonas pseudocorymbosa sp. nov. was described from Vietnam based on silica-scale morphology studied by transmission and scanning electron microscopy. This species belongs to the section Mallomonas. The distribution and habitat conditions of the new species were summarised. Mallomonas pseudocorymbosa was found in 17 localities in 13 provinces in Vietnam. A revision of the records in the tropical region of similar species Mallomonas corymbosa initially described from the arctic latitudes was made. All findings of Mallomonas corymbosa in the tropical region and the southern hemisphere belonged to Mallomonas pseudocorymbosa. Based on the available data, Mallomonas corymbosa has a northern temperate distribution.