bluuebunny/crossref_metadata_2025_split huggingface dataset:
Supplementary Figure S1 from Paclitaxel and Carboplatin in Combination with Low-intensity Pulsed Ultrasound for Glioblastoma
Authors: Habashy Karl J. , Dmello Crismita , Chen Li , Arrieta Victor A. , Kim Kwang-Soo , Gould Andrew , Youngblood Mark W. , Bouchoux Guillaume , Burdett Kirsten B. , Zhang Hui , Canney Michael , Stupp Roger , Sonabend Adam M. 
Published: April 2024

<p>Supplementary Figure 1. Paclitaxel delivered with low-intensity pulsed ultrasound and microbubbles leads to variable local tumor control.
Coronal T1 with contrast MRI images of patients from our phase I clinical trial (NCT04528680) who received the highest dose of Abraxane (260 mg/m2). We illustrate in green the area covered by the sonication, and observe a variable local tumor control within this region. The five patients presented in the upper (blue) panel exhibited tumor control, while the remaining patients (in red) had tumor growth while on therapy.</p>
Supplementary Figure 3 from CB307: A Dual Targeting Costimulatory Humabody V<sub>H</sub> Therapeutic for Treating PSMA-Positive Tumors
Authors: Archer Sophie , Brailey Phillip M. , Song Minjung , Bartlett Phillip D. , Figueiredo Ines , Gurel Bora , Guo Christina , Brucklacher-Waldert Verena , Thompson H. Lorraine , Akinwale Jude , Boyle Samantha E. , Rossant Christine , Birkett Neil R. , Pizzey Julia , Maginn Mark , Legg James , Williams Richard , Johnston Colette M. , Bland-Ward Philip , de Bono Johann S. , Pierce Andrew J. 
Published: April 2024

<p>Supplementary Figure 3: PK/TK dosing strategies</p>
Supplementary Figure 2 from CB307: A Dual Targeting Costimulatory Humabody V<sub>H</sub> Therapeutic for Treating PSMA-Positive Tumors
Authors: Archer Sophie , Brailey Phillip M. , Song Minjung , Bartlett Phillip D. , Figueiredo Ines , Gurel Bora , Guo Christina , Brucklacher-Waldert Verena , Thompson H. Lorraine , Akinwale Jude , Boyle Samantha E. , Rossant Christine , Birkett Neil R. , Pizzey Julia , Maginn Mark , Legg James , Williams Richard , Johnston Colette M. , Bland-Ward Philip , de Bono Johann S. , Pierce Andrew J. 
Published: April 2024

<p>Supplementary Figure 2: aCD137 antibody clone E6Z7F specificity</p>
Mutation Patterns Predict Drug Sensitivity in Acute Myeloid Leukemia
Authors: Qin Guangrong , Dai Jin , Chien Sylvia , Martins Timothy J. , Loera Brenda , Nguyen Quy H. , Oakes Melanie L. , Tercan Bahar , Aguilar Boris , Hagen Lauren , McCune Jeannine , Gelinas Richard , Monnat Raymond J. , Shmulevich Ilya , Becker Pamela S. 
Published: April 2024

Abstract

Purpose:
The inherent genetic heterogeneity of acute myeloid leukemia (AML) has challenged the development of precise and effective therapies. The objective of this study was to elucidate the genomic basis of drug resistance or sensitivity, identify signatures for drug response prediction, and provide resources to the research community.

Experimental Design:
We performed targeted sequencing, high-throughput drug screening, and single-cell genomic profiling on leukemia cell samples derived from patients with AML. Statistical approaches and machine learning models were applied to identify signatures for drug response prediction. We also integrated large public datasets to understand the co-occurring mutation patterns and further investigated the mutation profiles in the single cells. The features revealed in the co-occurring or mutual exclusivity pattern were further subjected to machine learning models.

Results:
We detected genetic signatures associated with sensitivity or resistance to specific agents, and identified five co-occurring mutation groups. The application of single-cell genomic sequencing unveiled the co-occurrence of variants at the individual cell level, highlighting the presence of distinct subclones within patients with AML. Using the mutation pattern for drug response prediction demonstrates high accuracy in predicting sensitivity to some drug classes, such as MEK inhibitors for RAS-mutated leukemia.

Conclusions:
Our study highlights the importance of considering the gene mutation patterns for the prediction of drug response in AML. It provides a framework for categorizing patients with AML by mutations that enable drug sensitivity prediction.
Abstract LT05: METTL8-MEDIATED EPITRANSCRIPTOMIC REGULATION OF GBM CYCLING STATE IS DEPENDENT ON RTK/PI3K/AKT SIGNALING
Authors: Lee Bernice Woon Li , Chuah You Heng , Yoon Jeehyun , Grinchuk Oleg V. , Feng Jia , Liang Yajing , Hirpara Jayshree L , Shen Ya Ting , Wang Loo Chien , Lim Yan Ting , Zhao Tianyun , Sobota Radoslaw M , Toh Tan Boon , Pervaiz Shazib , Lin Zhewang , Ong Derrick Sek Tong 
Published: April 2024

Abstract
Glioblastoma (GBM) is a lethal brain tumor with limited treatment options. Treatment failures are often attributed to the existence of glioma stem cells (GSCs), which confer intratumoral heterogeneity and therapy resistance. Contrary to common belief that cancer cells employ aerobic glycolysis (Warburg effect) to sustain their metabolic requirements, GSCs rely on oxidative phosphorylation (OXPHOS) for energy production. As a result, GSCs are uniquely sensitive to OXPHOS inhibitors (Gboxin), as well as mitochondrial translation inhibitors which disrupt OXPHOS. METTL8 is a newly discovered mitochondrial methyltransferase which catalyzes m3C32 modifications in mitochondrial tRNAsThr/Ser(UCN) (mt-tRNAs). This post-transcriptional modification ensures the optimal structure of mt-tRNAs to facilitate efficient translation of mitochondrial proteins involved in electron transport chain (ETC). Although the epitranscriptomic functions of METTL8 have been well characterized, its roles in cancers (i.e. glioblastoma) remain largely unexplored. In this study, we showed that METTL8 is overexpressed in GBM and high METTL8 expression portends poor patient prognosis. In GSC, METTL8 is under the transcriptional regulation of HIF-1α, and the chromatin accessibility at METTL8 promoter is facilitated by the deposition of histone variant H2AZ. METTL8 depletion downregulated m3C32 modifications in mt-tRNAsThr/Ser(UCN) in GSC, leading to impaired mitochondrial translation and OXPHOS defects. Phenotypically, METTL8 knockdown (KD) compromised GSCs’ self-renewal, proliferation, invasiveness and tumorigenicity. Interestingly, METTL8-KD GSC acquired a slow cycling state which is linked to reduced receptor tyrosine kinase (RTK) signaling. Consistently, METTL8-KD GSC showed lower Akt phosphorylation and exhibited increased sensitivity to mTOR/Akt inhibitors. Finally, our mechanistic findings led to the identification of a novel HIF1-α/Akt inhibitor drug combination which faithfully recapitulates the phenotypes of METTL8-KD GSCs. In conclusion, our findings provide the first in-depth study of METTL8 roles in GBM pathogenesis, and highlights a novel drug combination which could potentially be used to treat this dreadful disease.
Citation Format: Bernice Woon Li Lee, You Heng Chuah, Jeehyun Yoon, Oleg V. Grinchuk, Jia Feng, Yajing Liang, Jayshree L Hirpara, Ya Ting Shen, Loo Chien Wang, Yan Ting Lim, Tianyun Zhao, Radoslaw M Sobota, Tan Boon Toh, Shazib Pervaiz, Zhewang Lin, Derrick Sek Tong Ong. METTL8-MEDIATED EPITRANSCRIPTOMIC REGULATION OF GBM CYCLING STATE IS DEPENDENT ON RTK/PI3K/AKT SIGNALING [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr LT05.
Abstract P42: Beyond the Canonical: uORF-encoded Micro Peptides as Novel Kinase Inhibitors in Cancer Therapy
Authors: Jayaram Divya Ram , Frost Sigal , Argov Chanan , Liju Vijayasteltar Belsamma , Anto Nikhil Ponnoor , Muraleedharan Amitha , Ben-Ari Assaf , Sinay Rose , Smoly Ilan , Novoplansky Ofra , Isakov Noah , Toiber Debra , Keasar Chen , Elkabets Moshe , Yeger-Lotem Esti , Livneh Etta 
Published: April 2024

Abstract
About 40% of human mRNAs contain upstream open reading frames (uORFs) in their 5’-untranslated regions. Some of these uORF sequences thought to attenuate scanning ribosomes or lead to mRNA degradation were recently shown to be translated, although the function of most encoded peptides remains unknown. Our recent study was the first to reveal a uORF-encoded peptide exhibiting kinase inhibitory activity (Jayaram DR, et al. PNAS (2021)). This uORF (uORF2), upstream of a protein kinase C (PKC) family member (PKCeta) main ORF, encodes for a peptide (uPEP2) containing the typical PKC pseudosubstrate (PS) motif present in all PKCs that auto-inhibits their kinase activity. We show direct binding and selective inhibition of the catalytic activity of novel PKCs by uPEP2 (but not of classical or atypical PKCs). Functionally, treatment of breast cancer cells with uPEP2 diminished cell survival and their migration and synergized with chemotherapy by interfering with the response to DNA damage. Furthermore, in a xenograft of MDA-MB-231 triple-negative breast cancer in mice models, uPEP2 suppressed tumor progression, invasion, and metastasis. The endogenous deletion of uORF2 by CRISPR/Cas9 in the non-tumorigenic MCF-7 cells showed that it impedes cell proliferation, acting as a growth suppressor. Its role in tumor formation and metastasis is presently studied in breast cancer models with metastasis to the lungs. Together, we point to a new layer of protein regulation by a uORF-encoded kinase inhibitor, which could present a forerunner for other uORFs, possessing kinase inhibitory function. Notably, we have recently identified an additional uORF with a PS motif upstream of another PKC. As kinase inhibitors, uORF-encoded peptides may play a role in signaling and stress, acting in cis and/or in trans, forming diverse regulatory networks, thereby opening new views into eukaryotic protein regulation and cancer biology.
Citation Format: Divya Ram Jayaram, Sigal Frost, Chanan Argov, Vijayasteltar Belsamma Liju, Nikhil Ponnoor Anto, Amitha Muraleedharan, Assaf Ben-Ari, Rose Sinay, Ilan Smoly, Ofra Novoplansky, Noah Isakov, Debra Toiber, Chen Keasar, Moshe Elkabets, Esti Yeger-Lotem, Etta Livneh. Beyond the Canonical: uORF-encoded Micro Peptides as Novel Kinase Inhibitors in Cancer Therapy [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P42.
Abstract P58: Utilizing Cancer Vulnerabilities and Dependencies to Explore Cancer Biomarkers by Triangulating Large-Scale Gene Knockout and Drug Response Data
Authors: Yeo Shen Yong , Wong Wai Yee , Jesslyn  , Toh Tan Boon , Yang Valerie Shiwen , Woo Xing Yi 
Published: April 2024

Abstract
The identification of biomarkers of therapeutic response for different cancers presents significant challenges owing to the heterogeneity of these diseases. Whole-genome CRISPR gene knockout screening (DepMap) and large-scale drug dosing (e.g. PRISM, and Sanger GDSC) performed across large panels of cancer cell lines reveal a whole spectrum of cancer vulnerabilities and dependencies that can be used to identify potential biomarkers and perturbed pathways in subtypes of cancers.
In this study, we identified tumor type-specific dependent genes with CRISPR screening data. Functional relationships among genes were systematically examined by clustering genes with pronounced dependencies based on established biological pathways and conducting a co-dependency analysis. We found that both tumor type and subtype-specific analysis allowed the classification of cell lines based on gene dependency. Next, we correlated gene dependency of the selected dependent genes with normalised drug sensitivity scores (AUC) to triangulate potential biomarkers of drug response. We first applied this method to several tumor types which are well-characterised by known cancer drivers, and successfully identified known biomarkers and targeted pathways. However, we also identified previously unknown gene-drug relationships which will be further explored. Subsequent analysis of rarer cancers, including soft tissue sarcoma, yielded promising gene targets.
This analysis pipeline can be used extensively to mine DepMap data using any subset of cell lines of interest for biomarker discovery.
Citation Format: Shen Yong Yeo, Wai Yee Wong, Jesslyn, Tan Boon Toh, Valerie Shiwen Yang, Xing Yi Woo. Utilizing Cancer Vulnerabilities and Dependencies to Explore Cancer Biomarkers by Triangulating Large-Scale Gene Knockout and Drug Response Data [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P58.
Abstract P61: Distinct Roles of BRD4 Isoforms in Tumor Progression and Metastasis in Embryonal Rhabdomyosarcoma
Authors: Das Dipanwita , Yu Leung Jia , Loh Amos Hong Pheng , Taneja Reshma 
Published: April 2024

Abstract
The deregulation of BRD4, a bromodomain and extraterminal (BET) protein, has been implicated in various cancers, positioning it as a promising target for drug development. Yet, the specific roles of the two primary BRD4 isoforms, BRD4-L and BRD4-S, remain poorly understood across most cancer types. This knowledge gap poses challenges in assessing the effectiveness of pan-BET inhibitors as potential therapies. This study seeks to address this gap by employing functional and transcriptomic analyses to elucidate the distinct contributions of BRD4 isoforms in embryonal rhabdomyosarcoma (ERMS).
Through a comprehensive investigation, the research uncovers that BRD4-L and BRD4-S isoforms exert discrete functions in ERMS. Specifically, BRD4-L is found to exert an oncogenic role by inhibiting myogenic differentiation, partially through the activation of myostatin expression. Importantly, depletion of BRD4-L in vivo is shown to impede tumor progression without significantly affecting metastasis. In contrast, the absence of BRD4-S has an unexpected impact-while it has a minimal effect on tumor growth, it markedly enhances metastatic potential in vivo. Intriguingly, the depletion of BRD4-S leads to the heightened presence of BRD4-L and RNA Polymerase II at integrin gene promoters, consequently activating these genes. This novel insight underscores that BRD4-S acts as a gatekeeper, restraining the full scope of oncogenic activities driven by BRD4-L.
Collectively, this study reveals distinctive roles for BRD4 isoforms and uncovers a delicate interplay in ERMS. Importantly, the findings indicate that pan-BRD4 inhibition might not be the optimal therapeutic strategy for ERMS due to the intricate interplay between isoforms. By illuminating the intricate functions of BRD4 isoforms, this research advances our understanding of the complex regulatory mechanisms underlying tumor progression and metastasis in ERMS.
Citation Format: Dipanwita Das, Jia Yu Leung, Amos Hong Pheng Loh, Reshma Taneja. Distinct Roles of BRD4 Isoforms in Tumor Progression and Metastasis in Embryonal Rhabdomyosarcoma [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P61.
Alterações antropogeomorfológicas na bacia hidrográfica Córrego Lajeado, Campo Grande - MS
Authors: Capoane Viviane , Fushimi Melina 
Published: April 2024

A urbanização na bacia hidrográfica do Córrego Lajeado foi rápida e sem planejamento, o que desencadeou e/ou agravou impactos socioeconômicos e ambientais. Com o objetivo de gerar informações técnico-científicas para subsidiar o planejamento territorial e ambiental, este estudo realizou uma análise do relevo e do uso e cobertura da terra nesta bacia hidrográfica. Os atributos topográficos foram derivados de um Modelo Digital de Elevação (MDE) com resolução de 5 metros usando o software ArcMap e SAGA GIS. Os dados de uso e cobertura da terra para 1985 e 2021 foram obtidos da Rede MapBiomas. Índices radiométricos de vegetação foram derivados de imagens Sentinel-2 para o ano de 2021 usando o software SNAP. Os resultados obtidos mostram que a urbanização acelerou os processos morfodinâmicos, levando à criação de relevo antropogênico. Apesar de 50% da área da bacia estar localizada em uma Unidade de Conservação, que fornece 16% da água para a cidade de Campo Grande, a área está altamente degradada.
Buffering Mechanism in Aortic Arch Artery Formation and Congenital Heart Disease
Authors: Ramirez AnnJosette , Vyzas Christina A. , Zhao Huaning , Eng Kevin , Degenhardt Karl , Astrof Sophie 
Published: April 2024

BACKGROUND:
The resiliency of embryonic development to genetic and environmental perturbations has been long appreciated; however, little is known about the mechanisms underlying the robustness of developmental processes. Aberrations resulting in neonatal lethality are exemplified by congenital heart disease arising from defective morphogenesis of pharyngeal arch arteries (PAAs) and their derivatives.

METHODS:
Mouse genetics, lineage tracing, confocal microscopy, and quantitative image analyses were used to investigate mechanisms of PAA formation and repair.

RESULTS:

The second heart field (SHF) gives rise to the PAA endothelium. Here, we show that the number of SHF-derived endothelial cells (ECs) is regulated by
VEGFR2
(vascular endothelial growth factor receptor 2) and
Tbx1
. Remarkably, when the SHF-derived EC number is decreased, PAA development can be rescued by the compensatory endothelium. Blocking such compensatory response leads to embryonic demise. To determine the source of compensating ECs and mechanisms regulating their recruitment, we investigated 3-dimensional EC connectivity, EC fate, and gene expression. Our studies demonstrate that the expression of VEGFR2 by the SHF is required for the differentiation of SHF-derived cells into PAA ECs. The deletion of 1 VEGFR2 allele (

VEGFR2
SHF-HET

) reduces SHF contribution to the PAA endothelium, while the deletion of both alleles (

VEGFR2
SHF-KO

) abolishes it. The decrease in SHF-derived ECs in

VEGFR2
SHF-HET

and

VEGFR2
SHF-KO

embryos is complemented by the recruitment of ECs from the nearby veins. Compensatory ECs contribute to PAA derivatives, giving rise to the endothelium of the aortic arch and the ductus in

VEGFR2
SHF-KO

mutants. Blocking the compensatory response in

VEGFR2
SHF-KO

mutants results in embryonic lethality shortly after mid-gestation. The compensatory ECs are absent in
Tbx1
+/-
embryos, a model for 22q11 deletion syndrome, leading to unpredictable arch artery morphogenesis and congenital heart disease.
Tbx1
regulates the recruitment of the compensatory endothelium in an SHF-non-cell-autonomous manner.

CONCLUSIONS:
Our studies uncover a novel buffering mechanism underlying the resiliency of PAA development and remodeling.
The Magian Position: Legal Consequences for Creedal Ignorance in the Far Maghrib, 8th/14th-11th/17th century
Authors: Olson Caitlyn 
Published: April 2024

Abstract
This article analyzes a series of legal opinions from the Far Maghrib between the 8th/14th and 11th/17th centuries in which the authors promote a remarkable position: that members of the Muslim community deemed ignorant of creedal doctrine should be accorded the legal status of Magians (ḥukm al-majūs). The primary consequence of categorizing people as Magians – meaning here something different than Zoroastrians – was the annulment of their marriages. After discussing the sources and offering comments on the social, political, and religious circumstances that may have conditioned this position (Section 1), I explain its intellectual architecture. I show that while the concepts animating the concern with creedal ignorance were rooted in Ashʿarī theology (Section 2), the tools of enforcement came from Mālikī law (Section 3). The “Magian position” thus sheds light on historical interactions between Islamic theology and law, as well as on the functioning of orthodoxy in Muslim societies.
Comparison of 3 Different Surgical Techniques for Rotator Cuff Repair in a Rabbit Model: Direct Suture, Inlay Suture, and Polyether Ether Ketone (PEEK) Suture Anchor
Authors: Du Cancan , Chen Wei , Fang Jingchao , Zhang Yarui , Yan Wenqiang , Dai Wenli , Hu Xiaoqing , Ao Yingfang , Ren Shuang , Liu Zhenlong 
Published: April 2024

Background: Rotator cuff tears have been repaired using the transosseous method for decades. The direct suture (DS) technique has been widely used for rotator cuff tears; however, the retear rate is relatively high. Suture anchors are now used frequently for rotator cuff repair (RCR) in accordance with recent developments in materials. However, polyether ether ketone (PEEK) may still cause complications such as the formation of cysts and osteophytes. Some studies have developed the inlay suture (IS) technique for RCR. Purpose/Hypothesis: To compare how 3 different surgical techniques—namely, the DS, IS, and PEEK suture anchor (PSA)—affect tendon-bone healing after RCR. We hypothesized that the IS technique would lead to better tendon-to-bone healing and that the repaired structure would be similar to the normal enthesis. Study Design: Controlled laboratory study. Methods: Acute infraspinatus tendon tears were created in 36 six-month-old male rabbits, which were divided into 3 groups based on the technique used for RCR: DS, IS, and PSA. Animals were euthanized at 6 and 12 weeks postoperatively and underwent a histological assessment and imaging. The expression of related proteins was demonstrated by immunohistochemistry and immunofluorescence staining. Mechanical properties were evaluated by biomechanical testing. Results: At 12 weeks, regeneration of the enthesis was observed in the 3 groups. However, the DS group showed a lower type I collagen content than the PSA and IS groups, which was similar to the results for scleraxis. The DS group displayed a significantly inferior type II collagen expression and proteoglycan deposition after safranin O/fast green and sirius red staining. With regard to runt-related transcription factor 2 and alkaline phosphatase, the IS group showed upregulated expression levels compared with the other 2 groups. Conclusion: Compared with the DS technique, the PSA and IS techniques contributed to the improved maturation of tendons and fibrocartilage regeneration, while the IS technique particularly promoted osteogenesis at the enthesis. Clinical Relevance: The IS and PSA techniques may be more beneficial for tendon-bone healing after RCR.