bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B020: A mechanistic study of the TFE3-splicing machinery gene fusions reveals a new druggable target for translocation renal cell carcinoma
Authors: Fontane Ilaria Delle , Damayanti Nuri , Rupert Christopher , Heppner David E. , Pili Roberto 
Published: August 2023

Abstract
TFE3 is a member of basic helix-loop-helix leucine zipper MiT transcription factor family and its chimeric proteins are associated with translocation renal cell carcinoma (tRCC). Despite the variety of genes fusions, most of TFE3 fusions partner genes are linked to spliceosome machinery. Dissecting the function of TFE3 fused to spliceosome machinery factors (TFE3-SF) could direct the development of effective therapies for this lethal disease, which is refractory to standard treatments for kidney cancer. Here, by using a combination of in silico structure prediction, molecular cloning, next generation transcriptomics, FRET technology, mutagenesis, proteomics, and high-throughput high-content screening (HTHCS) we interrogated a series of oncogenic mechanisms of TFE3-SF-containing fusions, including spontaneous nuclear translocation, nuclear paraspeckle occupancy, enhanced in vitro proliferation and in vivo growth, transcriptome remodeling, alternative splicing reprogramming, and novel dimer partner recruitment. Molecular inhibition of TFE3-SF dimerization reverses its oncogenic activity and represents a potential new target for therapeutic intervention. Using HTHCS combined with FRET technology we screened FDA approved drugs library (LOPAC) and small molecule library (Microsource) and identified hits compounds which inhibit TFE3-SF dimerization. Hits compounds were validated in 2D and 3D models utilizing patient derived xenolines expressing TFE3-SF. Ouabain and terfenadine demonstrated decreased cell proliferation reduced spheroid growth and in vivo tumor growth. Overall, our results unmask synthetic vulnerabilities of TFE3-SF dimerization for novel therapeutic strategies in patients with this aggressive type of kidney cancer.
Citation Format: Ilaria Delle Fontane, Nuri Damayanti, Christopher Rupert, David E. Heppner, Roberto Pili. A mechanistic study of the TFE3-splicing machinery gene fusions reveals a new druggable target for translocation renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B020.
Abstract IA012: Modelling childhood cancer using organoid technology
Authors: Drost Jarno 
Published: August 2023

Abstract
Cancer is still one of the leading causes of disease-related deaths in children. Survivors suffer from side effects of the, in most cases, intensive treatment regimens. Hence, there is an urgent need to develop improved, less toxic therapies. Our vision is that if we understand the processes that underpin the development of childhood cancer, we will facilitate improved cure rates and a better quality of life. However, therapeutic innovation is hampered by the lack of cell models representative of native tumor tissue. The organoid technology has revolutionized cancer research, as it allows for the ‘unlimited’ expansion of healthy and diseased tissue from individual patients in a dish, while retaining essential characteristics of native tissue. Organoids are therefore seen as avatars of the tissues they were derived from (Drost & Clevers, Nat Rev Cancer 2018). We recently succeeded in establishing culture protocols to grow organoids from a wide spectrum of pediatric malignancies such as Wilms tumors, renal cell carcinomas, as well as different rhabdoid tumor and soft tissue sarcoma subtypes. Subjecting our models to a comprehensive molecular profiling, we were able to demonstrate that pediatric cancer organoids retain many features of the tissues they were derived from (Calandrini et al., Nat Commun 2020; Calandrini et al., Cell Rep 2021; Meister et al., EMBO Mol Med 2022; Paassen et al., Oncogene 2023). Thus, we massively expanded the number of relevant pre-clinical in vitro model systems for cancers for which models were rare or even non-existing, including different pediatric kidney cancer subtypes. We use these models in combination with genetic engineering and (single-cell) omics technologies to study the very fundamental processes underlying tumorigenesis with the aim to find new therapies.
Citation Format: Jarno Drost. Modelling childhood cancer using organoid technology [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr IA012.
Abstract IA016: Remodeling of tumor metabolism by L-2-hydroxyglutarate: Implications for renal cancer growth and progression
Authors: Sudarshan Sunil 
Published: August 2023

Abstract
Tumor cells remodel their metabolism to meet their unique demands in order to support tumor growth and progression. However, this reprogramming may create metabolic vulnerabilities. The small molecule L-2-hdroxyglutarate (L-2HG) is commonly elevated in clear cell renal cell carcinoma (ccRCC). Similar to other small molecules elevated in cancer, L-2HG has the potential to regulate gene expression by altering DNA, histone, and/or RNA methylation. Using unbiased profiling methodologies, we find that L-2HG remodels tumoral metabolism in renal cancer cells through the combined effects on histone methylation and RNA N6-methyladenosine (m6A). The combined effects of L-2HG result in a serine liability that renders tumors cells reliant on exogenous serine to support in vitro/vivo tumor growth and redox balance. In agreement with these data, raised L-2HG kidney tumors have reduced expression of serine biosynthetic enzymes. In summary, our data reveal that high L-2HG kidney tumors could be targeted by strategies that limit the availability of this now "essential" amino acid.
Citation Format: Sunil Sudarshan. Remodeling of tumor metabolism by L-2-hydroxyglutarate: Implications for renal cancer growth and progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr IA016.
Abstract IA028: Renal medullary carcinoma: Discovery and validation of tailored treatment strategies
Authors: Msaouel Pavlos 
Published: August 2023

Abstract
Renal medullary carcinoma (RMC) is a rare but highly aggressive malignancy that predominantly afflicts young individuals of African descent harboring the sickle cell trait and is defined by loss of the SMARCB1 tumor suppressor. Notably, the anti-VEGF and mTOR targeted therapies and standard immune checkpoint inhibitor strategies developed for clear cell renal cell carcinoma (ccRCC) are completely ineffective against RMC. Conversely, platinum-based cytotoxic chemotherapy regimens are the preferred first-line therapy yielding a response rate of 29% and median survival of 13 months from diagnosis. There is clearly a need for tailored treatment strategies for this deadly disease. To meet this challenge, we have developed a dedicated research and clinical team and bench-to-bedside pipeline that supported the comprehensive profiling of patient samples and the development of multiple RMC cell lines, three patient-derived xenografts, and the first genetically engineered mouse model of RMC. These tools informed the development of the first three clinical trials dedicated to RMC (NCT03587662, NCT03274258, and NCT05347212 at clinicaltrials.gov), as well as the establishment of effective second-line, and more recently third-line, therapeutic strategies that produce objective responses and occasionally cures for this deadly disease. Using these approaches, the majority of patients diagnosed with RMC today will survive beyond a year from diagnosis. The progress made has been supported by a passionate patient advocacy group and the awareness raised has resulted in our current clinical volume of caring for 3-5 patients with RMC per week. Emerging insights into the pathophysiology of RMC have allowed us to uncover an "exercise paradox" whereby the hypoxia induced by high-intensity exercise in the setting of sickle cell trait may be the strongest modifiable risk factor for RMC. The unique biological processes behind the exercise paradox also underlie the distinct biological adaptation of RMC to true hypoxia via the loss of SMARCB1, as opposed to the pseudohypoxia observed in ccRCC driven by VHL loss. Whereas pseudohypoxic tumors are sensitive to VEGF targeting, SMARCB1 loss confers resistance to the hypoxia induced by in vivo inhibition of angiogenesis. These insights have allowed us to identify immediately actionable therapeutic targets paving the way for the next generation of clinical trials for RMC. The benchmark goal is to improve the median survival of patients with RMC to 24 months by 2025 and to 5 years by 2030.
Citation Format: Pavlos Msaouel. Renal medullary carcinoma: Discovery and validation of tailored treatment strategies [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr IA028.
Abstract PR007: Von Hippel Lindau (VHL) tumor suppressor regulates m6A-dependent gene expression involved in renal tumorigenesis
Authors: Zhang Cheng , Zhang Zhao , Hepperla Austin , Yu Miaomiao , Zhou Jin , Hu Lianxin , Fang Jun , Liang Qian , Xu Kexin , Jia Liwei , Zhang Qing 
Published: August 2023

Abstract
Background: Renal cancer is the most common adult genitourinary cancer, of which ~85% is accounted for by the clear cell subtype (ccRCC). In the majority of ccRCC, as a result of VHL loss, HIF2a stabilization is sufficient and necessary for promoting ccRCC tumor growth. However, HIF-2 inhibitors have limited efficacy in cancer therapy, highlighting the importance of identifying additional therapeutic vulnerabilities. N6-Methyladenosine (m6A) is the most abundant internal post-translation modification, and its contribution to cancer evolution has just been appreciated. In renal cancer, previous research showed that m6A may play an important role but the molecular mechanism underlying m6A-regulated ccRCC tumorigenesis and aggression is still obscure. Approach and results: We demonstrate that VHL binds with m6A enzymatic complex proteins and regulates METTL3-METTL14 complex formation. VHL depletion suppresses mRNA m6A modification. By performing m6A RIP-Seq for renal cells with or without VHL coupled with RNA-Seq, we identified a selection of genes that their expression may be regulated by m6A. Specifically, PIK3R3 was identified to be one critical gene whose mRNA stability is regulated by VHL in a m6A-dependent but HIF-independent manner. Functionally, PIK3R3 depletion promoted renal cell growth and tumor growth while vice versa. Mechanistically, the VHL-m6A regulated PIK3R3 suppresses tumor growth by restraining PI3K/AKT activity. Conclusion: Taken together, we propose a new mechanism by which VHL regulates m6A through modulating METTL3-METTL14 protein complex formation, therefore promoting PIK3R3 mRNA stability and protein level that is critical for regulating ccRCC tumorigenesis.
Citation Format: Cheng Zhang, Zhao Zhang, Austin Hepperla, Miaomiao Yu, Jin Zhou, Lianxin Hu, Jun Fang, Qian Liang, Kexin Xu, Liwei Jia, Qing Zhang. Von Hippel Lindau (VHL) tumor suppressor regulates m6A-dependent gene expression involved in renal tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr PR007.
Abstract PR009: Linking VHL and SETD2 in a common oncogenic pathway that converges on the mitotic spindle
Authors: Dere Ruhee , Chowdhury Pratim , Jung Sung Yun , Aboulhassane Rim , Motrapu Manga , Wang Xiaoli , Han Richard , Walker Cheryl , Frew Ian , Rathmell W. Kimryn 
Published: August 2023

Abstract
Loss of chromosome 3p is a landmark event in clear cell renal cell carcinoma (ccRCC) that results in mono-allelic loss of VHL (von Hippel Lindau) and SETD2 (Set-domain containing 2) (and other tumor suppressors co-located on 3p). Second hits in VHL inactivate this key tumor suppressor initiating tumor progression. SETD2, a histone methyltransferase, was previously shown to have a dual function in methylating both histones and microtubules, thereby contributing to both the histone and tubulin codes. Methylation by SETD2 on microtubules occurs at the mitotic spindle and is essential for normal mitosis and cytokinesis, with loss of SETD2 acting as a strong driver of apoptosis. This raises a conundrum of how cancer cells survive early mono-allelic loss of SETD2, escaping cell death. We have identified the mitotic kinase, Aurora kinase A (AURKA), as a regulator of SETD2. Our data uncover SETD2 as a unique substrate for phosphorylation by AURKA, with mass spectrometry identifying serine 2080 (S2080) as the site of phosphorylation on SETD2. Phospho-SETD2 (S2080) localized at the spindle poles during mitosis, and this specific localization was modulated by AURKA enzymatic activity. Initial observations reveal a role for AURKA driven SETD2 phosphorylation at S2080 in nucleocytoplasmic shuttling of this methyltransferase. Our data suggest that phosphorylation of SETD2 by AURKA contributes to both its methyltransferase (i.e. enzymatic) activity and its geo-spatial location with the cell. Importantly, AURKA expression levels are high in VHL-null cells resulting from an inability of VHL to target AURKA for degradation and our data now highlight a direct link between VHL and SETD2, two tumor suppressors believed to independently drive RCC pathogenesis. In summary, our data reveal a tumor-specific vulnerability linked to mitotic fragility that can be precisely targeted to ultimately drive mitotic catastrophe.
Citation Format: Ruhee Dere, Pratim Chowdhury, Sung Yun Jung, Rim Aboulhassane, Manga Motrapu, Xiaoli Wang, Richard Han, Cheryl Walker, Ian Frew, W. Kimryn Rathmell. Linking VHL and SETD2 in a common oncogenic pathway that converges on the mitotic spindle [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr PR009.
Abstract PR013: An integrative genomics approach converges on a critical OXPHOS program driven by MiT/TFE fusions in translocation renal cell carcinoma
Authors: Li Jiao , Gallant Danny S. , Sadagopan Ananthan , Li Bingchen , Xu Qingru , Viswanathan Srinivas R. 
Published: August 2023

Abstract
Translocation renal cell carcinoma (tRCC) is a rare and aggressive subtype of non-clear cell renal cell carcinoma (RCC) that represents 1-5% of kidney cancer in adults. Biologically, tRCC is driven by rearrangements that involve a member of the MiT/TFE transcription factor gene family, most commonly TFE3. There are currently no molecularly-targeted therapies specific to tRCC, owing in part to an incomplete mechanistic understanding of precisely how MiT/TFE gene fusions exert their oncogenic function. In prior work, we leveraged “histologic overlap” between tRCC and other RCC subtypes to identify tRCC cases from across multiple genomic, clinical trial, and retrospective RCC datasets, with the goal of defining the molecular landscape of this disease. Here, by analyzing pathways selectively activated in tRCC relative to other RCC subtypes in this aggregate dataset, we observed that tRCCs display strong enrichment for genes involved in oxidative phosphorylation (OXPHOS), reactive oxidative species (ROS) sensing, and the response to oxidative stress mediated by the transcription factor NRF2 (nuclear factor erythroid-derived2-like 2 [NFE2L2]). We performed chromatin immunoprecipitation and sequencing (ChIP-Seq) on a panel of tRCC and clear-cell RCC (ccRCC) cell lines, using antibodies against TFE3 as well as the active enhancer mark H3K27ac. We found that tRCC cell lines display a distinctive epigenomic profile characterized by activation of a host of genes involved in driving OXPHOS as well as NRF2 signaling. We further found that TFE3 fusions and NRF2 physically interact and genomically co-localize at multiple genes critical for mediating the response to antioxidant stress, suggesting that this metabolic phenotype is transcriptionally driven by TFE3 fusions. Genome-scale CRISPR screening in tRCC cell lines subsequently revealed tRCC-selective vulnerabilities in components of the OXPHOS machinery and in the NRF2 pathway, a distinction from most other kidney cancers in which aerobic glycolysis predominates. Overall, our genomic and functional studies implicate an essential transcriptional program driven by TFE3 fusions that converges on activation of the OXPHOS and NRF2 pathways. These molecular features provide mechanistic rationale for exploring the therapeutic targeting of OXPHOS and/or redox homeostasis pathways in tRCC.
Citation Format: Jiao Li, Danny S. Gallant, Ananthan Sadagopan, Bingchen Li, Qingru Xu, Srinivas R. Viswanathan. An integrative genomics approach converges on a critical OXPHOS program driven by MiT/TFE fusions in translocation renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr PR013.
Hemodynamic Predictors of Outcome Following Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy
Authors: Alabdaljabar Mohamad S. , Cendrowski Emily E. , Nishimura Rick A. , Miranda William R. , Geske Jeffrey B. , Rihal Charanjit S. , Eleid Mackram F. 
Published: August 2023

BACKGROUND:
Alcohol septal ablation (ASA) is a minimally invasive treatment for drug-refractory obstructive hypertrophic cardiomyopathy. Detailed assessment of pressure changes and predictors of mortality and procedure success are not well defined.

METHODS:
This is a single-center study evaluating pressure changes and predictors of mortality and procedure success in transseptal ASA. Survival analysis and predictors of mortality were assessed using the Kaplan-Meier analysis and Cox regression, respectively.

RESULTS:

A total of 156 patients were included (mean age, 67.3 years; 46.8% women). Left atrial (LA) pressure and left ventricular outflow tract (LVOT) gradient decreased, whereas aortic pulse pressure (PP) increased post-ASA. Patients with lower baseline mean LA pressure (<median, 19 mm Hg), LVOT gradient reduction >82% (gradient change median), and PP increase >19% (PP change median) had superior survival. On Cox univariable regression, baseline mean LA pressure >median (19 mm Hg; hazard ratio [HR], 2.09 [95% CI, 1.05–4.18];
P
=0.036), residual LVOT gradient (HR, 1.02 [95% CI, 1.01–1.03];
P
=0.003), and LVOT gradient percent reduction <median (82%; HR, 2.92 [95% CI, 1.46–5.83];
P
=0.002) were predictors of mortality. When adjusting for age and sex, baseline LA v wave >median (28 mm Hg; HR, 2.36 [95% CI, 1.17–4.76];
P
=0.016), baseline mean LA pressure >median (19 mm Hg; HR, 2.70 [95% CI, 1.33–5.50];
P
=0.006), percentage reduction in gradient <median (82%; HR, 2.74 [CI, 1.37–5.50];
P
=0.005), and percentage increase in PP <median (19.3%; HR, 2.09 [CI, 1.05–4.16];
P
=0.035) predicted survival free of all-cause mortality.

CONCLUSIONS:
ASA is associated with an acute decrease in the LVOT gradient and LA pressures and increase in aortic PP. Mean LA pressure, percentage decrease in LVOT gradient, and increase in PP are strong predictors of survival free of all-cause mortality following ASA and are important variables for procedural guidance.
Evil Powers, Exodus, and Future Deliverance
Authors: Kister Menahem 
Published: August 2023

Abstract
In the present article, I argue that a passage from the Damascus Document (CD 4:12–16 + 5:15–19) and an opaque saying attributed to Jesus (Luke 11:20) mutually illuminate each other. The starting point of both is the conception that a conflict between God and the evil power(s) took place before the Exodus. An analogy is drawn between this period and the present liminal period considered as the beginning of the eschatological period prior to the eschaton. The expectations for healing and resurrection in the eschaton in 4Q521 2 ii 8, 11–12 shed light on Matt 11:3 // Luke 7:19. When viewed through the lens of the conception that the eschatological period has already commenced, these expectations were transformed to Jesus’s activity in the present.
Characterization of the complete mitochondrial genome of Aristaeopsis edwardsiana (Decapoda, Dendrobranchiata) and the phylogenetic implications for Aristeidae
Authors: Liang Xinjie , Sun Yuman , Ye Yingying , Li Jiji 
Published: August 2023

Abstract
We analysed the mitochondrial genome of Aristaeopsis edwardsiana (Johnson, 1868) to understand its origin and evolution. Our study uncovered new insights into its phylogenetic relationships and evolutionary history. The mitogenome of A. edwardsiana is 15 913 bp, contains 37 genes, including 13 protein-coding genes (PCGs), 2 ribosomal RNA genes (rRNA) and 22 transfer RNA genes (tRNA). The AT content is 64.98%, with negative AT and GC skews. Our analysis showed that the PCGs of A. edwardsiana and related Aristeidae species underwent purifying selection. The tRNA genes exhibited a typical structure, except trnC and trnS1. The gene order was conserved compared to ancestral decapods. Using species of Dendrobranchiata, we constructed a phylogenetic tree, revealing the relationship of A. edwardsiana within the family Aristeidae. These findings improve our understanding of Decapoda classification and Aristeidae’s evolutionary position, facilitating further phylogenetic investigations. This study may serve as a valuable reference for future research on species of Aristeidae.
What Does a Kohen Have to Do with the Protocols of the Ashkenazic Community of Amsterdam? A Conflict between Community Sanctity and the Righteousness of the Ancients
Authors: Yedidya Asaf 
Published: August 2023

Abstract
This article deals with an incident in the Ashkenazic community of Amsterdam in 1772 that was documented in the protocols of the community. A member of the congregation confessed to the rabbi after the death of her husband, a kohen, that she was in fact a convert. The rabbi informed her son that as the son of a kohen married to a convert he was defined as a ḥalal (disqualified), and thereby lost his status as a kohen. A few weeks later, the rabbi and his bet din (Jewish tribunal) were required to reconsider the halakhic significance of the mother’s testimony about herself and the status of her children and came to the opposite conclusion, that the mother was not a convert and her son was indeed a kohen. The article discusses the possible reasons for re-examining a halakhic question that had already been decided and for reversing the decision, while clarifying the founding ethos of the community, its style of conduct, and the nature of its records. Finally I speculate about what lay behind the mother’s admission.