bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4494: Multi-specific cMet x EGFR x VEGF antibody for difficult to treat cancers
Authors: Chiu Mark 
Published: April 2023

Abstract
Cancers such as TNBC, pancreatic, and gastric are difficult to treat due to diverse etiologies. Several subtypes of these cancers are driven by abnormal EGFR signaling, increased cMET activation, and VEGF linked angiogenesis which are responsible for tumor growth and metastasis. TAVO412, a humanized multi-specific antibody with two distinct anti-EGFR nanobody domains, an anti-cMet Fab arm, and an anti-VEGF ScFv domain, was designed to treat patients with these unmet medical needs. In addition, the Fc domain allows for the heterodimerization, antibody-like pharmacokinetic profile, and additional mutations that enhance the Fc effector functional activity. In preclinical xenograft models, TAVO412 demonstrated strong tumor growth inhibition effects on TNBC, PDAC, GC or NSCLC cell line-derived tumors. The mechanisms of action included selective and potent binding to EGFR, cMet, and VEGF at lower pH values found in the solid tumor environment; effective blocking of EGFR and cMet pathways that drove cancer cell growth and proliferation; shutdown of VEGF mediated angiogenesis; and potent and efficacious Fc effector function that enhanced ADCC, ADCP, and CDC. TAVO412 had better TGI than analogous molecules. TAVO412 also demonstrated strong tumor growth inhibition against NSCLC patient derived xenograft (PDX) models with mutant EGFR and cMet genotypes. Each of the binding arms had cross reactivity with the cynomolgus monkey orthologues allowing the cyno model to be a relevant toxicology model. In the pivotal GLP toxicology study in cynomolgus monkeys, TAVO412 was well tolerated, had no major organ toxicities, observations were mostly consistent with EGFR-related effects and recoverable. In conclusion, TAVO412 was successfully discovered and developed for hard-to-treat solid tumors. This drug is expected to be safe and efficacious in cancer patients. The IND application was approved by the US FDA in October 2022. A first-in-human, 2-Part Phase 1 study to examine the preliminary efficacy, safety, tolerability, pharmacokinetic/pharmacodynamic parameters; maximum tolerated dose/recommended phase 2 dose of TAVO412 will be starting in the first quarter of 2023.
Citation Format: Mark Chiu. Multi-specific cMet x EGFR x VEGF antibody for difficult to treat cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4494.
Abstract 4724: Single cell multiomic profiling of high-grade serous carcinoma
Authors: Sandoval Leticia Assad Maia , Ismail Wazim Mohammed , Mazzone Amelia , Munankarmy Amik , Kaur Jagneet , Tashi Tsering , Hou Xiaonan , Kannan Nagarajan , Oberg Ann , Kaufmann Scott H. , Weroha Saravut John , Gaspar-Maia Alexandre 
Published: April 2023

Abstract
Ovarian cancer is one of the most common gynecologic malignancies, with high-grade serous carcinoma (HGSC) as the most frequent and deadliest type of ovarian cancer (OC). With the recent advances in cancer epigenomic profiling, it has become clear that intra-tumor heterogeneity driven by genetic and epigenetic factors may be the basis of resistance, where current treatments could efficiently target sub-populations of cells while a sub-group may be resistant, or prone to develop resistance. With epigenomic profiling and single cell sequencing technology, we aim to characterize cell signatures that translate as prognostic markers and novel drug targets. We have mapped the epigenomic landscape of HGSC in 12 patient-derived xenografts (PDX), and their metastatic counterparts (circulating tumor cells and ascites present in the PDX models) using an assay for transposase-accessible chromatin (or ATAC-seq) and compared it with normal fallopian tube organoids to identify tumor and metastatic-specific regulatory elements. We also performed RNA-seq to validate potential transcriptional dependencies associated with resistance to chemotherapy. In order to identify potentially chemotherapy-resistant subpopulations and further validate the activity of some of the transcription factors that can be driving resistance, we performed single cell multiomic profiling using the 10x Multiome sequencing platform (scRNA+scATAC from the same nuclei) in HGSC patient samples and PDX. Finally, we performed immunohistochemistry of patient tissue slides for target markers and correlated it with overall survival in OC patients. As previously suggested, a subset of cancer clonal cells can drive treatment resistance and metastasis and result in poor patient outcomes. Data derived from PDX ATAC-seq showed a cancer stem cell signature driven by SOX2 in metastatic samples compared to the paired PDX primary tumor, suggesting a role for SOX2 in disease progression. Interestingly, SOX2 expression in epithelial cells in the Multiome analysis is more patient-specific than other stem cell markers, like CD133. We also observed that SOX2 expression negatively correlated with prognosis. These data, taken together, point out the promising role of SOX2 as a prognostic and targetable marker for HGSC.
Citation Format: Leticia Assad Maia Sandoval, Wazim Mohammed Ismail, Amelia Mazzone, Amik Munankarmy, Jagneet Kaur, Tsering Tashi, Xiaonan Hou, Nagarajan Kannan, Ann Oberg, Scott H. Kaufmann, Saravut John Weroha, Alexandre Gaspar-Maia. Single cell multiomic profiling of high-grade serous carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4724.
Abstract 7: AGS3 depletion promotes tumorigenesis in a murine model of lung cancer
Authors: Adekoya Timothy O. , Smith Nikia , Richardson Ricardo M. 
Published: April 2023

Abstract
Activator of G-protein Signaling 3 (AGS3/GPSM1) is a receptor independent activator of G-protein signaling that couples to Gα subunits of the heterotrimeric G-protein to mediate cellular functions. It was previously shown that AGS3 modulates prostate tumor development. In this study we investigate the role of AGS3 in the onset of lung cancer. To that end, we used a murine model of Lung Lewis Carcinoma (LLC) in mice deficient in AGS3 expression (AGS3-/-) relative to wild-type animals (AGS3+/+). AGS3-/- mice exhibited a significant increase in LLC tumor growth relative to AGS3+/+ mice. Immunohistochemical analysis of the tumors also revealed a significant increase in microvessels density in AGS3-/- tumors. FACS analysis of tumor infiltrating leukocytes also showed a significant decrease in lymphocyte recruitment in AGS3-/- tumor microenvironment (TME) relative to AGS3+/+ mice. The decrease leukocytes recruitment in AGS3-/- xenografts correlated with a marked decrease in chemokines expression in the TME. Taken together, these results indicate that AGS3 modulates LLC tumor development and progression.
Citation Format: Timothy O. Adekoya, Nikia Smith, Ricardo M. Richardson. AGS3 depletion promotes tumorigenesis in a murine model of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 7.
Abstract 99: Apoptotic DNase DFFB mediates cancer persister cell mutagenesis and acquired drug resistance
Authors: Williams August Finley , Gervasio David , Turkal Claire , Stuhlfire Anna , Wang Michael , Mauch Brandon , West Ariel , Paw Michelle , Hairani Mehrshad , Lathrop Cooper , Harris Sophie , Page Jennifer , Hangauer Matthew 
Published: April 2023

Abstract
Tumors frequently acquire resistance to therapy resulting in disease relapse and patient mortality. Therapeutic approaches to overcome acquired resistance are hindered by limited treatment options and the presence of multiple parallel resistance mechanisms. Rather than treating resistance after it emerges, it may possible to prevent it by inhibiting the adaptive processes which initiate resistance. However, these processes and the genes which control them are poorly understood. Here we report that drug-tolerant cancer persister cells, which constitute residual disease and seed relapse, undergo drug stress-induced sublethal apoptotic signaling resulting in activation of apoptotic DNase DFFB without cell death. DFFB induces DNA damage and mutagenesis in persister cells, revealing DFFB as a key regulator of stress-induced mutagenesis in persister cells. Furthermore, we found in multiple tumor types that DFFB is required for acquired resistance to targeted therapies. Mechanistically, DFFB induces multiple putative resistance mutations and may also promote epigenetic changes which result in resistance. These results reveal DFFB as a promising potential therapeutic target to prevent acquired resistance. In addition, this stress-sensing mutagenic mechanism may promote mutagenesis in other contexts including normal tissues because sublethal apoptotic signaling may result from a variety of physiological stresses.
Citation Format: August Finley Williams, David Gervasio, Claire Turkal, Anna Stuhlfire, Michael Wang, Brandon Mauch, Ariel West, Michelle Paw, Mehrshad Hairani, Cooper Lathrop, Sophie Harris, Jennifer Page, Matthew Hangauer. Apoptotic DNase DFFB mediates cancer persister cell mutagenesis and acquired drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 99.
Genetic Determinants of the Interventricular Septum Are Linked to Ventricular Septal Defects and Hypertrophic Cardiomyopathy
Authors: Yu Mengyao , Harper Andrew R. , Aguirre Matthew , Pittman Maureen , Tcheandjieu Catherine , Amgalan Dulguun , Grace Christopher , Goel Anuj , Farrall Martin , Xiao Ke , Engreitz Jesse , Pollard Katherine S. , Watkins Hugh , Priest James R. 
Published: April 2023

Background:
A large proportion of genetic risk remains unexplained for structural heart disease involving the interventricular septum (IVS) including hypertrophic cardiomyopathy and ventricular septal defects. This study sought to develop a reproducible proxy of IVS structure from standard medical imaging, discover novel genetic determinants of IVS structure, and relate these loci to diseases of the IVS, hypertrophic cardiomyopathy, and ventricular septal defect.

Methods:
We estimated the cross-sectional area of the IVS from the 4-chamber view of cardiac magnetic resonance imaging in 32 219 individuals from the UK Biobank which was used as the basis of genome wide association studies and Mendelian randomization.

Results:

Measures of IVS cross-sectional area at diastole were a strong proxy for the 3-dimensional volume of the IVS (Pearson
r
=0.814,
P
=0.004), and correlated with anthropometric measures, blood pressure, and diagnostic codes related to cardiovascular physiology. Seven loci with clear genomic consequence and relevance to cardiovascular biology were uncovered by genome wide association studies, most notably a single nucleotide polymorphism in an intron of
CDKN1A
(rs2376620; β, 7.7 mm
2
[95% CI, 5.8–11.0];
P
=6.0×10
−10
), and a common inversion incorporating
KANSL1
predicted to disrupt local chromatin structure (β, 8.4 mm
2
[95% CI, 6.3–10.9];
P
=4.2×10
−14
). Mendelian randomization suggested that inheritance of larger IVS cross-sectional area at diastole was strongly associated with hypertrophic cardiomyopathy risk (p
IVW
=4.6×10
−10
) while inheritance of smaller IVS cross-sectional area at diastole was associated with risk for ventricular septal defect (p
IVW
=0.007).

Conclusions:
Automated estimates of cross-sectional area of the IVS supports discovery of novel loci related to cardiac development and Mendelian disease. Inheritance of genetic liability for either small or large IVS, appears to confer risk for ventricular septal defect or hypertrophic cardiomyopathy, respectively. These data suggest that a proportion of risk for structural and congenital heart disease can be localized to the common genetic determinants of size and shape of cardiovascular anatomy.
Longitudinal Trends in Cardiovascular Risk Factor Profiles and Complications Among Patients Hospitalized for COVID-19 Infection: Results From the American Heart Association COVID-19 Cardiovascular Disease Registry
Authors: Hall Eric J. , Ayers Colby R. , Kolkailah Ahmed A. , Rutan Christine , Walchok Jason , Williams Joseph H. , Wang Tracy Y. , Rodriguez Fatima , Bradley Steven M. , Stevens Laura , Hall Jennifer L. , Mallya Pratheek , Roth Gregory A. , Morrow David A. , Elkind Mitchell S.V. , Das Sandeep R. , de Lemos James A. 
Published: April 2023

Background:
The COVID-19 pandemic has evolved through multiple phases characterized by new viral variants, vaccine development, and changes in therapies. It is unknown whether rates of cardiovascular disease (CVD) risk factor profiles and complications have changed over time.

Methods:
We analyzed the American Heart Association COVID-19 CVD registry, a national multicenter registry of hospitalized adults with active COVID-19 infection. The time period from April 2020 to December 2021 was divided into 3-month epochs, with March 2020 analyzed separately as a potential outlier. Participating centers varied over the study period. Trends in all-cause in-hospital mortality, CVD risk factors, and in-hospital CVD outcomes, including a composite primary outcome of cardiovascular death, cardiogenic shock, new heart failure, stroke, and myocardial infarction, were evaluated across time epochs. Risk-adjusted analyses were performed using generalized linear mixed-effects models.

Results:

A total of 46 007 patient admissions from 134 hospitals were included (mean patient age 61.8 years, 53% male, 22% Black race). Patients admitted later in the pandemic were younger, more likely obese, and less likely to have existing CVD (
P
trend
≤0.001 for each). The incidence of the primary outcome increased from 7.0% in March 2020 to 9.8% in October to December 2021 (risk-adjusted
P
trend
=0.006). This was driven by an increase in the diagnosis of myocardial infarction and stroke (
P
trend
<0.0001 for each). The overall rate of in-hospital mortality was 14.2%, which declined over time (20.8% in March 2020 versus 10.8% in the last epoch; adjusted
P
trend
<0.0001). When the analysis was restricted to July 2020 to December 2021, no temporal change in all-cause mortality was seen (adjusted
P
trend
=0.63).

Conclusions:
Despite a shifting risk factor profile toward a younger population with lower rates of established CVD, the incidence of diagnosed cardiovascular complications of COVID increased from the onset of the pandemic through December 2021. All-cause mortality decreased during the initial months of the pandemic and thereafter remained consistently high through December 2021.
Musical Evidence for Low Boundary Tones in Ancient Greek
Authors: Gunkel Dieter 
Published: April 2023

Abstract
Several scholars have suggested that in ancient Greek there was a low boundary tone at the end of a relatively small prosodic constituent such as a clitic group or maximal prosodic word. The boundary tone may phonologically motivate some puzzling pitch-accentual phenomena in the language. One is the diachronic pitch-peak retraction that led to the circumflex pitch accent (HL) on penultimate syllables (the “sōtêra rule”). Another is the intonational phrase-internal downstepping or deletion of a word-final acute accent (H); that conversion of an acute to a grave accent is known as “lulling” or “koímēsis”. If such a low boundary tone existed, its effects should still be audible in ancient Greek non-strophic vocal music, where there is a significant correlation between the pitch movement of the text and the movement of the melody to which it is set, i.e. between tone and tune. Specifically, proponents of such a low boundary tone would predict that the turning point between falling and rising melody, the “musical trough”, should center around the word-final mora or syllable. The present study provides the first full description of troughs in the Delphic Hymns and finds that they are indeed closely aligned with word-end. Furthermore, once other factors that could lead to word-final troughs are set aside, i.e. once potential confounds are controlled for, the association of the trough with word-end remains strong, suggesting that we should in fact reconstruct the low boundary tone.
Telling, Gathering and (Re)Experiencing Stories: Video Interview as Methodology and Innovation in Practitioner-Based Research
Authors: Dunham Nicola , Chant Lisa 
Published: April 2023

Abstract
This article explores the use of video as both an interview technique for data collection and for research dissemination. Attention is given to ways in which video interviews gathered as part of the Maraea community research project were reframed in the development of a virtual reality experience. Maraea is a research project conducted between 2017–2020. A comparative methodology was used to gather knowledge on indigenous-health-practitioner-led community-based solutions from New Zealand, Australia, Canada and the USA that focus on whānau rangatiratanga / family self-determination. Although the video interviews have been disseminated through an official Maraea website, the authors explored ways to reframe or (re)experience the stories being told. An immersive virtual reality (vr) prototype was created to explore the potential to bring the user / learner / audience closer to the narrative, to the practitioner telling their story and therefore to the practices being shared.
Wallace Stevens
Authors: Hederman Mark Patrick 
Published: April 2023

Abstract
This paper hopes to show that, for Wallace Stevens, God and human imagination are closely identified. Moreover, the feeling of rightness, which for so long a time existed with the old religious idea of God, may be accessed once again. His notion of the “supreme fiction” will compare with Descartes’ “idea of the Infinite” as interpreted by Emmanuel Levinas. This epistemological reality, central to our being, can also become contemporary to our lives, in a way that the old religious idea of God can never again be. With access to this “right idea,” we may again find the sort of solace that we once found in old religious beliefs.
The Use of Small Uncrewed Aircraft System Observations in Meteorological and Dispersion Modeling
Authors: Ngan Fong , Loughner Christopher P. , Zinn Sonny , Cohen Mark , Lee Temple R. , Dumas Edward , Schuyler Travis J. , Baker C. Bruce , Maloney Joseph , Hotz David , Mathews George 
Published: April 2023

Abstract
A series of meteorological measurements with a small uncrewed aircraft system (sUAS) was collected at Oliver Springs Airport in Tennessee. The sUAS provides a unique observing system capable of obtaining vertical profiles of meteorological data within the lowest few hundred meters of the boundary layer. The measurements benefit simulated plume predictions by providing more accurate meteorological data to a dispersion model. The sUAS profiles can be used directly to drive HYSPLIT dispersion simulations. When using sUAS data covering a small domain near a release and meteorological model fields covering a larger domain, simulated pollutants may be artificially increased or decreased near the domain boundary because of inconsistencies in the wind fields between the two meteorological inputs. Numerical experiments using the Weather Research and Forecasting (WRF) Model with observational nudging reveal that incorporating sUAS data improves simulated wind fields and can significantly affect mixing characteristics of the boundary layer, especially during the morning transition period of the planetary boundary layer. We conducted HYSPLIT dispersion simulations for hypothetical releases for three case study periods using WRF meteorological fields with and without assimilating sUAS measurements. The comparison of dispersion results on 15 and 16 December 2021 shows that using sUAS observational nudging is more significant under weak synoptic conditions than under strong influences from regional weather. Very different dispersion results were introduced by the meteorological fields used. The observational nudging produced not just an sUAS-nudged wind flow but also adjusted meteorological fields that further impacted the mixing calculation in HYSPLIT.
Clinical Application of the Residual Thyroid Cartilage for Laryngeal Function Reconstruction in the Partial Laryngectomy—A Single Center Experience
Authors: Li Pingdong , Zhou Jing , Yang Zheng , Chen Xuejun , Chen Xiaohong , Huang Zhigang 
Published: April 2023

BackgroundTo investigate the outcomes of using the residual thyroid cartilage for laryngeal function reconstruction in early glottic laryngeal carcinoma.MethodsFrom March 2017 to June 2022, 21 patients with glottic carcinoma who underwent laryngeal function reconstruction were analyzed retrospectively. The operation was performed under general anesthesia. Reconstruction of ipsilateral hemilarynx defect by downward movement of ipsilateral residual thyroid cartilage plate. During the follow-up period, the laryngeal function and tumor recurrence were evaluated.Resultsotally 20 male patients and 1 female patient were enrolled in this study. Of the 20 initial primary tumors, there were 6 patients with T1N0M0 stage, 12 ones with T2N0M0 stage, 1 with T1N1M0 stage, 1 with T3N0M0 stage, and 1 with T2N1M0 stage. The patient with recurrent tumor was T3N1M0 stage. The follow-up time ranged from 9 to 63 months. All patients were healed by first intention after surgery. All patients without laryngeal stenosis were removed from tracheotomy tube. So far, all patients have good laryngeal function. One patient relapsed at the last follow-up.ConclusionIt is safe to repair hemilarynx defect with residual thyroid cartilage plate on the affected side, and it is an important choice for laryngeal function reconstruction after vertical partial laryngectomy.
Alterations of commensal microbiota are associated with pancreatic cancer
Authors: Chen Tian , Li Xuejiao , Li Gaoming , Liu Yun , Huang Xiaochun , Ma Wei , Qian Chao , Guo Jie , Wang Shuo , Qin Qin , Liu Shanrong 
Published: April 2023

Background Dysbiosis commonly occurs in pancreatic cancer, but its specific characteristics and interactions with pancreatic cancer remain obscure. Materials and methods The 16S rRNA sequencing method was used to analyze multisite (oral and gut) microbiota characteristics of pancreatic cancer, chronic pancreatitis, and healthy controls. Differential analysis was used to identify the pancreatic cancer-associated genera and pathways. A random forest algorithm was adopted to establish the diagnostic models for pancreatic cancer. Results The chronic pancreatitis group exhibited the lowest microbial diversity, while no significant difference was found between the pancreatic cancer group and healthy controls group. Diagnostic models based on the characteristics of the oral (area under the curve (AUC) 0.916, 95% confidence interval (CI) 0.832-1) or gut (AUC 0.856; 95% CI 0.74, 0.972) microbiota effectively discriminate the pancreatic cancer samples in this study, suggesting saliva as a superior sample type in terms of detection efficiency and clinical compliance. Oral pathogenic genera ( Granulicatella, Peptostreptococcus, Alloprevotella, Veillonella, etc.) and gut opportunistic genera ( Prevotella, Bifidobacterium, Escherichia/Shigella, Peptostreptococcus, Actinomyces, etc.), were significantly enriched in pancreatic cancer. The 16S function prediction analysis revealed that inflammation, immune suppression, and barrier damage pathways were involved in the course of pancreatic cancer. Conclusion This study comprehensively described the microbiota characteristics of pancreatic cancer and suggested potential microbial markers as non-invasive tools for pancreatic cancer diagnosis.