bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B003: Increasing branched-chain amino acid metabolism reduces clear cell renal cell carcinoma growth
Authors: Coffey Nathan J. , Riscal Romain , Skuli Nicolas , Lesner Nicholas P. , Noji Michael , Jiang Christine , Kim Laura C. , Han Xu , Blair Megan C. , Keith Brian , Arany Zoltan , Simon M. Celeste 
Published: August 2023

Abstract
North America has the highest incidence of renal cancer in the world with the most common subtype being clear cell renal cell carcinoma (ccRCC). Metabolic dysfunction is a hallmark of ccRCC based on molecular analysis and its clear cell histologic appearance due to significant cytoplasmic accumulation of lipid droplets and glycogen. Using publicly available RNA-Seq and proteomic datasets, we identified reduced expression of branched-chain amino acid (BCAA) enzymes BCAA transaminase 2 (BCAT2) and the branched-chain ketoacid dehydrogenase complex (BCKDH) in ccRCC compared to healthy kidney tissue. We validated these results by confirming that BCAT2 and the BCKDH complex are decreased at the mRNA and protein level in ccRCC tumors and cell lines compared to pair-matched normal adjacent kidney tissue. The reduced expression of the BCKDH complex was reinforced at the genome level by copy number loss of BCKDH subunits DBT and BCKDHB, underscoring the selection for suppression of this pathway. Metabolomics analysis then showed that the abundance of BCAAs were decreased in ccRCC tumors. Additionally, public datasets revealed that ccRCC patients presenting low mRNA expression of any of the four BCKDH subunits DBT, BCKDHB, BCKDHA, and DLD have a worse overall survival compared to patients with higher expression. To test if reactivating the BCAA pathway would impact ccRCC growth, I inhibited BCKDK, a kinase that inactivates the BCKDH complex, pharmacologically with BT2 and genetically with shRNA. Multiple ccRCC cell lines demonstrated reduced proliferation due to apoptosis after being treated with shRNA targeting BCKDK. Cell viability could be rescued by the antioxidant N-acetyl cysteine, suggesting loss of BCKDK increased the production of reactive oxygen species (ROS). Flow cytometry showed that knocking down BCKDK increases cellular ROS. Our data reveal that BCAA catabolism is decreased in ccRCC and reactivating the pathway reduces ccRCC growth in vitro by inducing apoptosis through increased production of ROS. This suggests that BCKDK could be a therapeutic target in ccRCC.
Citation Format: Nathan J. Coffey, Romain Riscal, Nicolas Skuli, Nicholas P. Lesner, Michael Noji, Christine Jiang, Laura C. Kim, Xu Han, Megan C. Blair, Brian Keith, Zoltan Arany, M. Celeste Simon. Increasing branched-chain amino acid metabolism reduces clear cell renal cell carcinoma growth [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 B003.
Abstract B016: SETD2 safeguards the genome against isochromosome formation
Authors: Mason Frank M. , Tebeje Anteneh T. , Kounlavong Emily S. , Dahiya Rashmi , Vlach Logan , Guess Tiffany , Dere Ruhee , Ohi Ryoma , Ly Peter , Walker Cheryl L. , Rathmell W. Kimryn 
Published: August 2023

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR012) of the Conference Program/Proceedings.
Citation Format: Frank M. Mason, Anteneh T. Tebeje, Emily S. Kounlavong, Rashmi Dahiya, Logan Vlach, Tiffany Guess, Ruhee Dere, Ryoma Ohi, Peter Ly, Cheryl L. Walker, W. Kimryn Rathmell. SETD2 safeguards the genome against isochromosome formation [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 B016.
Abstract B026: Combined inhibition of mammalian target of rapamycin (mTOR) and survivin augments radiation therapy in renal cell carcinoma
Authors: Pal Krishnendu , Madamsetty Vijay S. , Rachamala Hari K. , Dutta Shamit K. , Wang Enfeng , Mukhopadhyay Debabrata 
Published: August 2023

Abstract
Purpose: Although renal cell carcinoma (RCC) is relatively more resistant to radiation therapy (RT) compared to other cancer indications, recent advances in single-fraction and multi-fraction stereotactic ablative radiotherapy (SABR) made it possible to achieve better outcome and reduce treatment related toxicities. In addition, with studies demonstrating that certain therapeutic agents including chemotherapies can act as radiosensitizers, the idea of combining radiotherapy with those agents are being actively pursued. Among them, mammalian target of rapamycin (mTOR) inhibitor everolimus (E) and survivin inhibitor YM155 (Y) are of special interest since they target multiple RT-resistance mechanisms simultaneously. Additionally, YM155 has been shown to help in overcoming resistance to mTOR inhibitors in various cancer including RCC. Hence, the present study aims to evaluate the efficacy of a tumor-targeted liposomal formulation combining everolimus and YM155 (EY-L) in sensitizing RCC tumors towards radiation. Experimental Design: Previously we developed a tumor-targeted liposomal formulation and used it successfully to deliver multiple drugs for the treatment of RCC in both immune-deficient and immune-competent mouse models. Here we developed a similar formulation combining everolimus and YM155 (EY-L) and assessed its efficacy in RCC cell lines in vitro and in RCC tumors in vivo. We further evaluated the efficacy of EY-L in sensitizing RCC cell lines and tumors towards radiation in vitro using clonogenic assay and in vivo in RCC xenografts in immunodeficient mice and murine RCC models in immunocompetent mice. Results: EY-L (2 mg/kg E, 1.4 mg/kg Y, twice a week intravenous administration) was better than E-L or Y-L, the corresponding single drug loaded formulations in containing the primary tumor growth and improving survival in an immunocompetent syngeneic mouse model of RCC. Furthermore, EY-L leads to significantly higher sensitization of RCC cells towards radiation in vitro than E-L or Y-L. Finally, EY-L was able to sensitize RCC tumors towards radiation therapy in both RCC xenograft and murine RCC model. Conclusion: Taken together, our study demonstrated the efficacy of a strategic combination therapy in sensitizing RCC to radiation therapy using in vitro clonogenic assay and in vivo radiosensitization studies in multiple RCC tumor models.
Citation Format: Krishnendu Pal, Vijay S. Madamsetty, Hari K. Rachamala, Shamit K. Dutta, Enfeng Wang, Debabrata Mukhopadhyay. Combined inhibition of mammalian target of rapamycin (mTOR) and survivin augments radiation therapy in 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 B026.
Abstract B028: Tipifarnib synergizes with axitinib in renal cell carcinoma models
Authors: Gatchalian Jovylyn , Kessler Linda , Patel Hetika Vora , Chan Stacia , Burrows Francis , Malik Shivani 
Published: August 2023

Abstract
Clear cell renal cell carcinoma (ccRCC) is a highly vascularized tumor type, primarily due to loss of the Von Hippel-Lindau (VHL) gene that stabilizes hypoxia-inducible factor alpha proteins (HIF1α and HIF2a), primary drivers of the angiogenic response in this cell type. This includes production of angiogenic factors, such as VEGFA, which promotes the formation of blood vessels that provide tumors oxygen, nutrients, and growth factors. Anti-angiogenic tyrosine kinase inhibitors (TKIs) such as the VEGFR1/2/3 inhibitor axitinib have demonstrated therapeutic benefit in RCC patients by exploiting the critical dependency of RCC tumors on their vasculature. However, resistance to TKIs is commonly observed, leading to clinical relapse. Here, we report that the farnesyltransferase inhibitor (FTI), tipifarnib synergizes with axitinib, resulting in tumor regressions in the VHL-mutant RCC cell line-derived xenograft (CDX) models, 786-O and A498, and stasis in VHL-wild type Caki1 CDX and KI-9310 PDX models, despite the modest antitumor activity of either drug as monotherapy. To investigate the mechanism underlying this synergism, we performed immunohistochemical analysis of angiogenic markers in 786-O tumors treated with tipifarnib, axitinib, or the combination. Consistent with its mechanism of action, axitinib alone decreased angiogenesis compared to vehicle, which was evident as reduced expression of endothelial cell (EC) markers in the tumors. The combination of tipifarnib and axitinib, however, led to a further two-fold reduction in EC staining, suggesting that tipifarnib is enhancing the anti-angiogenic effect of axitinib. Further in vitro and in vivo studies are underway to establish the scope and mechanistic underpinnings of the axitinib-tipifarnib effects in RCC.
Citation Format: Jovylyn Gatchalian, Linda Kessler, Hetika Vora Patel, Stacia Chan, Francis Burrows, Shivani Malik. Tipifarnib synergizes with axitinib in renal cell carcinoma models [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 B028.
Abstract IA001: Evidence for a ‘pathway tuning’ model of VHL-associated renal carcinoma
Authors: Ratcliffe Peter J. 
Published: August 2023

Abstract
In clear cell renal carcinoma (RCC), the hypoxia inducible factor (HIF) transcriptional response is unphysiologically activated by mutations that impair or inactivate the von Hippel-Lindau tumour suppressor, which normally acts as a ubiquitin E3 ligase promoting the oxygen dependent proteolysis of hypoxia inducible factor (HIF). The lecture will review evidence for pro- and anti-tumourigenic actions arising from different components of HIF pathway activation in the setting of VHL-associated RCC. This includes evidence from genome-wide association studies (GWAS) that demonstrate a striking association of GWAS signals with cis-acting sequences in the HIF transcriptional system. This supports a ‘pathway tuning’ model in which multiple small selective effects are important in enabling cancer progression in the face of unphysiological activation of very extensive biological pathways. To assess this hypothesis a new experimental model has been developed, which enables the precise tracking of Vhl-inactivated cells. Results on the temporal and spatial effects of Vhl inactivation in kidneys will be presented.
Citation Format: Peter J. Ratcliffe. Evidence for a ‘pathway tuning’ model of VHL-associated renal 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 IA001.
Abstract IA007: A novel strategy to trigger ferroptosis in kidney cancer
Authors: Koh Mei Yee 
Published: August 2023

Abstract
Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is typically initiated by inactivation of the von Hippel Lindau (VHL) gene resulting in constitutive activation of the hypoxia inducible factors, HIF-1α and HIF-2α. VHL loss and HIF activation promote lipid accumulation that increases the sensitivity of ccRCC cells to ferroptosis. Here, we reveal Iron Sulfur Cluster Assembly 2 (ISCA2) as a novel molecular target whose inhibition decreases HIF-1/2α levels and induces ferroptosis specifically in VHL-deficient cells. ISCA2 is a component of the late mitochondrial Iron Sulfur Cluster (L-ISC) assembly complex and ISCA2 inhibition either pharmacologically or using siRNA triggers the iron starvation response, resulting in iron/metals overload and death via ferroptosis. ISCA2 inhibition also decreases HIF-2α protein levels by blocking iron-responsive element (IRE)-dependent translation, and at higher concentrations, also decreases HIF-1α translation through unknown mechanisms. Strikingly, pharmacological inhibition of ISCA2 using a novel, orally available ISCA2 inhibitor significantly reduced ccRCC xenograft growth in vivo, decreased HIF-α levels and increased lipid peroxidation, suggesting increased ferroptosis in vivo. Thus, the targeting of ISCA2 may be a promising therapeutic strategy to inhibit HIF-1/2α and to induce ferroptosis in pVHL deficient cells.
Citation Format: Mei Yee Koh. A novel strategy to trigger ferroptosis in kidney cancer [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 IA007.
Abstract IA020: Exploiting cholesterol metabolism for treatment resistant ccRCC patients
Authors: Simon M. Celeste 
Published: August 2023

Abstract
Clear cell renal cell carcinoma (ccRCC) is characterized by large intracellular lipid droplets (LDs) comprised primarily of free and esterified cholesterol molecules; however, the functional significance of cholesterol accumulation in ccRCC cells was unknown. We demonstrated that, surprisingly, genes encoding cholesterol biosynthetic pathway enzymes are strongly repressed in ccRCC cells, making them auxotrophic for exogenous cholesterol. Intriguingly, Mendelian randomization analyses of over 31,000 human genomes indicate a causal link between elevated serum levels of high-density lipoprotein (HDL) cholesterol and ccRCC risk. Depriving ccRCC cells of either cholesterol or HDL compromises proliferation and survival in vitro and ccRCC tumor growth in vivo; in contrast, elevated dietary cholesterol promotes tumor growth. We showed that Scavenger Receptor B1 (SCARB1) is uniquely required for cholesterol import by ccRCC cells, and inhibiting SCARB1 expression or activity is sufficient to cause ccRCC cell cycle arrest and apoptosis accompanied by elevated intracellular reactive oxygen species (ROS) levels and decreased PI3K/AKT signaling. Collectively, our data reveal a previously unrecognized cholesterol dependency in ccRCC and implicate SCARB1 as a therapeutic target that may contribute to novel strategies for treating kidney cancer.
Citation Format: M. Celeste Simon. Exploiting cholesterol metabolism for treatment resistant ccRCC patients [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 IA020.
Abstract IA027: New advances in the pathogenesis of renal cell carcinoma in tuberous sclerosis and Birt-Hogg-Dubé syndrome
Authors: Henske Elizabeth 
Published: August 2023

Abstract
Tuberous Sclerosis Complex (TSC) is caused by either TSC1 or TSC2 mutations, resulting in tumors of the brain, heart, skin, and kidney with hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1). Renal cell carcinomas (RCC) in TSC have chromophobe-like histology features. In TSC2-deficient cells, mTORC1 activity toward its canonical (Raptor-dependent) substrates is increased, while the phosphorylation of non-canonical substrates such as TFEB is decreased, leading to nuclear localization and increased activity of TFEB. Remarkably, treatment with the mTORC1 inhibitor Rapamycin or downregulation of Rheb or Raptor shifts the balance of mTORC1 activity toward the non-canonical substrates in TSC2-deficient cells, leading to increased phosphorylation of TFEB and decreased TFEB activity. Knockout of Tfeb abolishes renal pathology in two mouse models of TSC, indicating that this substrate specificity is the critical mediator of renal disease in TSC. Together, our results indicate that the TSC protein complex controls a critical switch in mTORC1 substrate specificity upstream of Rheb and the Rags, and the effects of rapamycin in TSC are mediated by the paradoxical increased activity of mTORC1 towards the non-canonical target TFEB. These findings may shed light on the sporadic form of chromophobe RCC, which is derived from the renal intercalated cells and has several mysterious features including mitochondrial abundance, whole chromosome losses, and high levels of glutathione (50-100 times higher than matched normal kidney). We hypothesize that hyperactivation of TFEB and/or TFE3 may represent a “missing link” to chromophobe RCC, which highly express lysosomal genes and proteins, thereby connecting chromophobe RCC to TSC-associated and BHD-associated RCC and to translocation RCC.
Citation Format: Elizabeth Henske. New advances in the pathogenesis of renal cell carcinoma in tuberous sclerosis and Birt-Hogg-Dubé syndrome [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 IA027.
Abstract PR006: STING is a vulnerability in RCC independent of its innate immunity function
Authors: Liu Pengda , Zhu Zhichuan 
Published: August 2023

Abstract
STING is an innate immune sensor for immune surveillance of viral/bacterial infection and maintenance of an immune-friendly microenvironment to prevent tumorigenesis. However, if and how STING exerts innate immunity-independent function remains elusive. Recently, we find STING expression is increased in renal cell carcinoma (RCC) patients and governs tumor growth through non-canonical innate immune signaling involving mitochondrial ROS maintenance and calcium homeostasis. We identify mitochondrial voltage dependent anion channel VDAC2 as a new STING binding partner. STING depletion potentiates VDAC2/GRP75-mediated MERC (mitochondria-ER contact) formation to increase mitochondrial ROS/calcium levels, impairs mitochondria function and suppresses mTORC1/S6K signaling leading to RCC growth retardation. STING interaction with VDAC2 occurs through STING-C88/C91 palmitoylation and inhibiting STING palmitoyl-transferases ZDHHCs by 2-BP significantly impedes RCC cell growth alone or in combination with sorafenib. Together, our studies reveal an innate immunity-independent function of STING in regulating mitochondrial function and growth in RCC, providing a rationale to target the STING/VDAC2 interaction in treating RCC.
Citation Format: Pengda Liu, Zhichuan Zhu. STING is a vulnerability in RCC independent of its innate immunity function [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 PR006.
Clinical Benefit of Autologous Stem Cell Transplantation for Patients with Multiple Myeloma Achieving Undetectable Minimal Residual Disease after Induction Treatment
Authors: Liu Jiahui , Yan Wenqiang , Fan Huishou , Xu Jingyu , Li Lingna , Du Chenxing , Mao Xuehan , Yan Yuting , Xu Yan , Sui Weiwei , Deng Shuhui , Yi Shuhua , Anderson Kenneth C. , Qiu Lugui , Zou Dehui , An Gang 
Published: August 2023

Attaining undetectable minimal residual disease (MRD) is the current therapeutic goal for multiple myeloma. But there is a current lack of data regarding the clinical benefit of autologous stem cell transplantation (ASCT) for patients with myeloma achieving early MRD-negative status after induction treatment, in addition to the interaction of longitudinal MRD status with ASCT. The current study included 407 patients with transplant-eligible multiple myeloma with available MRD status from the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199), of whom 147 (34.4%) achieved early undetectable MRD and 182 (44.7%) received ASCT. Early MRD-negative status was associated with a lower risk of disease progression [HR = 0.447; 95% confidence interval (CI), 0.333–0.600; P &lt; 0.001] and death (HR = 0.473; 95% CI, 0.320–0.700; P &lt; 0.001). Of note, patients who achieved undetectable MRD early still benefitted from ASCT, with a remarkable improvement in the median MRD-negative duration (33.5–58.0 months, P &lt; 0.001), progression-free survival (PFS; 46.0–88.3 months, P &lt; 0.001), and overall survival (OS; 76.4 months to not reached, P = 0.003). These clinical benefits were more pronounced in patients with aggressive features (high-risk cytogenetic abnormalities or high tumor burden) compared with standard-risk patients. Similar results were observed in patients with detectable MRD after induction treatment. In addition, we identified four MRD-status transformation patterns following ASCT, which were strongly correlated with diverse survival outcomes (P &lt; 0.001). Our study revealed the enhanced clinical significance of ASCT in patients with transplant-eligible myeloma, regardless of early MRD status, particularly for high-risk patients. Subsequent prospective trials are essential to validate these observations.

Significance:
Achieving and maintaining undetectable MRD is the current treatment goal for multiple myeloma. Our results emphasized the remarkable clinical benefit of ASCT on MRD-negative duration, PFS, and OS in patients with multiple myeloma regardless of early MRD status. These favorable impacts were more evident in patients with aggressive features. Importantly, dynamic MRD monitoring among ASCT could facilitate personalized stratification of therapeutic approaches.
The Conquest of the Temple Scroll and the Creation of the Scholarly Text
Authors: Borchardt Francis 
Published: August 2023

Abstract
The story of the discovery of the Temple Scroll, frequently retold, is a gripping tale. It mixes archaeology with espionage, and even military victory. In that sense, it is unique. However, in other ways, it participates in conventions of discovery narratives nearly as old as writing itself. Like ancient find accounts, it establishes a provenance for the manuscript, details the labor involved in making the discovery available, and seeks to raise interest in the contents of the scroll. This all functions as a means of elevating the value of the text. This article argues that the narrative of the Temple Scroll’s discovery also performs another important function: it re-creates the scroll as a text ripe for scholarly analysis. In so doing, the narrative erases and/or diminishes the acts of translation and mediation necessary to accomplish this transformation from material to textual object.
The Passive Participle ‮כתוב‬‎—A Citation or Keyword Formula?
Authors: Klukowski Michal 
Published: August 2023

Abstract
The analysis of the uses of the passive participle ‮כתוב‬‎ in the halakhic section of MMT shows that the ‮כתוב‬‎ formula introduces keywords rather than summative quotations. By quoting keywords, the authors of MMT enable their addressee to easily identify a passage from Scripture. The way in which the scriptural passage is quoted suggests that the words introduced by the formula have been selected so that they are appropriate for only one passage, and that the addressee knows perfectly well to which passage the author refers. The selection of keywords does not allow us to note any exegetical act in it; it is only about quoting a text, which in itself is an argument in the polemic.
The Subdivision of Boys in the Leonidean Decree (IG V.1 19)
Authors: Bai Shanshan 
Published: August 2023

Abstract
This paper examines two problematic appellations of boy victors, παῖς καθαρός and παῖς κρίσεως τῆς Ἀγησιλάου, and the subdivision of boys in the Spartan festival Leonidea in inscription IG V.1 19. I propose several emendations to the edition of this inscription with the hope to correct a mistake and add two events into the athletic contest. I argue that age and birth were important criteria for the sub-classification of παῖδες, whereas physical development did not play a major role in the process. By means of adopting different categorizations in different games, Sparta memorialized its heroes, both warriors in the past Persian war and contemporary benefactors, innovated its traditions of athletic training and contests, and displayed its reputation of excellence in the Leonidea.