bluuebunny/crossref_metadata_2025_split huggingface dataset:
Copper and zinc isotopic compositions of methane-derived carbonates: Implications for paleo-methane seepage and paleoenvironmental proxies
Authors: Zhang Ganglan , Deng Yinan , Chen Fang , Li Ming , Cao Jun , Lai Hongfei , Zhu Yangtao , Yang Shengxiong , Liang Qianyong , Kuang Zenggui , Fang Yunxin , Liu Yufei , Jiang Xuexiao , Zhao Mingyu 
Published: March 2024

Abstract
Copper-zinc isotopic excursions in carbonate sedimentary successions are used to trace oceanic chemistry fluctuations that occurred in the geological past. However, whether carbonate sediments can accurately record the Cu-Zn isotopic compositions of coeval seawater is still a matter of debate. We analyzed the Cu-Zn isotopic compositions of well-characterized methane-derived carbonates from drill cores in the South China Sea to decode the effect of the sedimentary environment on Cu-Zn isotopic fractionation. All seep carbonates have uniform δ65Cuauth values (the per mil deviation of the 65Cu/63Cu ratio from the NIST 976 standard; −0.22‰ to 0‰) independent of the sedimentary environment. In contrast, the δ66Znauth values (the per mil deviation of the 66Zn/64Zn ratio from the JMC-Lyon standard) of seep carbonates that precipitated from bottom seawater (intense methane seepage; 0.59‰ to 1.03‰) are significantly higher than those that formed in pore-water environments (low methane flux; −0.07‰ to 0.41‰). This evidence implies that changes in sedimentary environments can affect the Zn isotopic fractionation of carbonate sediments. Furthermore, the strong sedimentary environment-dependent Zn isotopic fractionation proves the validity of using Zn isotopes as a robust proxy for tracing paleo-methane seepage intensity caused by gas hydrate dissociation.
Gravitational perturbation in nonlocal modified Tolman VII model
Authors: Jayawiguna Byon N. , Burikham Piyabut 
Published: March 2024

AbstractIn comparison to the original Tolman VII model, Exact Modified Tolman VII (EMTVII) with one additional parameter can increase the compactness of compact object. When the compactness is in the ultracompact regime, the quasinormal modes (QNMs) of the trapped mode as well as the gravitational echoes become more viable. Starting with the EMTVII model, we introduce nonlocality into the matter sector and analyze the effective potential, the QNMs, and the gravitational echoes of the compact and ultracompact object in the nonlocal model. The nonlocal gravity version of EMTVII (NEMTVII) is parametrized by the nonlocal parameter ($$ \beta $$
β
), modified Tolman VII parameter ($$ \alpha $$
α
), and the compactness ($$ {\mathcal {C}}$$
C
). It is found that the nonlocal profile produces the smeared surface and consequently reduce the compactness. The maximum compactness $${\mathcal {C}}_{max}=0.4$$

C

max

=
0.4

occurs when $$\alpha =0=\beta $$

α
=
0
=
β

, i.e., EMTVII with no smearing. For relatively small value of $$\beta = 0.01$$

β
=
0.01

and the compactness $$ {\mathcal {C}} \lesssim 0.2667$$

C
≲
0.2667

(with $$M=2.14$$

M
=
2.14

solar masses, $$R=11.835$$

R
=
11.835

km at $$\alpha =1.4$$

α
=
1.4

), the causality condition and the dominant energy condition (DEC) are satisfied. The quasinormal modes of the gravitational perturbation are calculated using Bohr-Sommerfeld (BS) fitting and we find that the nonlocality produces less trapped modes than the original (EMTVII) counterpart. At high compactness, gravitational echoes are simulated numerically. Echoes are found to exist in the parameter space where the dominant energy condition and the causality condition are violated.
Abstract A015: Predicting efficacious drugs and drug-biomarker relationships for targeted glioblastoma treatment
Authors: Maeser Danielle , Gruener Robert , Galvin Robert , Huang Stephanie , Koga Tomo , Grigore Florina 
Published: March 2024

Abstract
Glioblastoma multiforme (GBM) is the deadliest, most heterogeneous, and common brain cancer in adults. Despite major advancements in neurosurgery as well as chemotherapy and radiotherapy techniques, overall prognosis has changed little over the decades. Not only is there an urgent need to identify efficacious therapeutics but there is also a great need to pair these therapeutics with biomarkers that can help tailor treatment to the right patient populations given the heterogeneous nature of the disease. Here, we implement several machine learning and statistical based pipelines for drug and biomarker discovery, leveraging previous work building patient drug response models using high-throughput cell line drug screening data as well as Bayesian network structure learning. Through these discovery pipelines, we identified multiple agents of interest for GBM, including MEK inhibitors (MEKis). MEKis were consistently predicted to be effective against GBM in multiple cross platform (microarray and RNA-sequencing) patient and patient derived xenograft (PDX) datasets. Additionally, they were experimentally shown to be more efficacious in tumor samples than standard of care agents (Temozolomide and Carmustine). We also predicted PHGDH gene expression levels to be causally associated with MEKi efficacy, which increased tumor sensitivity to a MEKi (Trametinib) during experimental testing in GBM cell lines with knockdown. These findings support our drug and biomarker discovery pipelines as an effective strategy to unite multiple cross platform and cross species datasets to help achieve GBM precision medicine. They also demonstrate that patient PHGDH levels can help inform Trametinib response in the fight against GBM.
Citation Format: Danielle Maeser, Robert Gruener, Robert Galvin, Stephanie Huang, Tomo Koga, Florina Grigore. Predicting efficacious drugs and drug-biomarker relationships for targeted glioblastoma treatment [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A015.
Abstract A033: Murine CNS and bone marrow distribution of the aurora A kinase inhibitor alisertib: Pharmacokinetics and exposure at the sites of efficacy and toxicity
Authors: Oh Juhee , Power Erica A. , Zhang Wenjuan , Daniels David J. , Elmquist William F. 
Published: March 2024

Abstract
Important challenges in developing drugs that target central nervous system (CNS) tumors include overcoming barriers for CNS delivery and reducing systemic side effects. Alisertib, an aurora A kinase inhibitor, has been examined for treatment of several CNS tumors in preclinical and clinical studies. In this study, we investigated the distribution of alisertib into the CNS, the site of efficacy for brain tumors, and into the bone marrow, the site of dose-limiting toxicity leading to myelosuppression. Mechanisms influencing site-specific distribution, such as active transport mediated by the efflux proteins, p-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), were examined. Alisertib exposure to the brain in wild-type mice was less than 1% of that in the plasma and was evenly distributed throughout various brain regions and the spinal cord. Studies using transporter knockout mice and pharmacological inhibition show that alisertib CNS distribution is influenced by P-gp, but not Bcrp. Conversely, upon systemic administration, alisertib distribution to the bone marrow occurred rapidly, was not significantly limited by efflux transporters, and reached higher concentrations than in the CNS. This study demonstrates that, given an equivalent distributional driving force exposure in plasma, the exposure of alisertib in the brain is significantly less than that in the bone marrow, suggesting that targeted delivery may be necessary to guarantee therapeutic efficacy with minimal risk for adverse events. Therefore, these data suggest that, to improve the therapeutic index when using alisertib for brain tumors, a localized regional delivery, such as convection-enhanced delivery, may be warranted.
Citation Format: Juhee Oh, Erica A. Power, Wenjuan Zhang, David J. Daniels, William F. Elmquist. Murine CNS and bone marrow distribution of the aurora A kinase inhibitor alisertib: Pharmacokinetics and exposure at the sites of efficacy and toxicity [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A033.
Abstract B022: Interplay between the cellular dntp pool and dna double-strand break repair: a potential therapeutic target for refractory glioblastoma
Authors: Monroe Dominique , Usoro Edidiong , Williams Arilyn , Aycox Shelby , Steinbeck Emily , Daddacha Waaqo 
Published: March 2024

Abstract
Glioblastoma (GBM) is a deadly brain tumor resistant to double-strand break (DSB)-inducing therapeutics due to dysregulated DNA-repair. Ionizing radiation (IR) and some chemotherapeutics strategically target cancer cells by causing DNA-DSBs, resulting in cell death if left insufficiently repaired. Homologous Recombination (HR) is an error-free DSB-repair process consisting of proteins that are often dysregulated in GBM, causing overactive DNA-repair, therapy resistance, and poor patient outcomes. Proteins involved in the HR-repair process have been extensively investigated; however, therapeutic resistance remains common. Here, we provide an alternative approach to target DSB-resistant GBM by modulating the dNTP pool instead of only targeting DNA-repair proteins. Our goal is to understand the interplay between dNTP pools and DSB-repair. dNTPs are a necessary constituent to repair DSBs; however, the role of the dNTP pool in DNA damage repair is not fully understood. Previous research shows that the dNTP pool remains unchanged after inducing DSBs, highlighting the importance of a tightly regulated dNTP pool. Our results show that increasing the dNTP pool significantly increased apoptosis and reduced cancer cell viability after IR. We found that a higher cellular dNTP pool impaired HR-mediated DSB-repair by delaying DNA end-resection in HR. Filling this gap in our knowledge may provide new avenues to sensitize therapy-resistant cancers, enhancing the efficacy of DSB-inducing therapies.
Citation Format: Dominique Monroe, Edidiong Usoro, Arilyn Williams, Shelby Aycox, Emily Steinbeck, Waaqo Daddacha. Interplay between the cellular dntp pool and dna double-strand break repair: a potential therapeutic target for refractory glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B022.
Abstract B032: Designing arrays for the mouse head to facilitate in vivo studies of Tumor Treating Fields (TTFields) treatment of glioblastoma
Authors: Zbidat Sewar , Blatt Roni , Sellevoll Mariell , Gabay Martin , Schlachet Inbar , Cahal Shay , Davidi Shiri , Tzchori Itai , El-Mabhouh Amal , Haber Adi , Giladi Moshe , Palti Yoram 
Published: March 2024

Abstract
Background: Tumor Treating Fields (TTFields) therapy is a noninvasive, anticancer treatment delivered by two pairs of arrays placed on the skin surrounding the tumor location. Based on efficacy and safety data from phase 3 global clinical studies, TTFields therapy is FDA-approved and CE marked for treatment of glioblastoma (GBM), the most common malignant brain tumor. In vivo studies of TTFields in GBM models, which are mostly based on mice, are complicated by the relatively small size of the mouse head and corresponding limited surface area to apply the arrays. This challenge has thus far limited in vivo research on TTFields treatment in GBM. Materials and Methods: To identify a method for efficient delivery of TTFields to the mouse brain, we examined the ability of different array layouts to accommodate the geometries of the mouse head while minimally impacting head movement, taking into account that it may not be feasible to place two pairs of arrays on the head. The properties of different adhesive tapes, specifically their ability to attach to the skin, was also investigated. Finally, the ability of array layouts to deliver therapeutic intensities to the desired region was validated using simulations and direct electric field measurements. Results: Assessments showed an optimal layout consisted of arrays such that one of the pair was on the mouse head, and the other on the mouse torso; and the arrays for placement on the head divided into two smaller disks, A thin, transparent adhesive tape was identified that allowed the arrays to be securely attached to the skin, but was easily removed without leaving residues. Validation studies using simulations demonstrated that the array layout met the minimum treatment requirements (field intensity ≥1 V/cm RMS; current ≥50 mA), and facilitated TTFields usage for ≥75% of each day. Conclusions: These data show that TTFields treatment can be effectively delivered to the heads of mice by utilizing carefully designed arrays. Our newly developed mouse head arrays are a flexible construct, that adheres strongly to the skin, and enables efficient electric field delivery to the mouse brain. These improvements in the delivery of TTFields treatment to mice will facilitate research of TTFields as a therapy for GBM.
Citation Format: Sewar Zbidat, Roni Blatt, Mariell Sellevoll, Martin Gabay, Inbar Schlachet, Shay Cahal, Shiri Davidi, Itai Tzchori, Amal El-Mabhouh, Adi Haber, Moshe Giladi, Yoram Palti. Designing arrays for the mouse head to facilitate in vivo studies of Tumor Treating Fields (TTFields) treatment of glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B032.
Abstract PR-001: Beta-adrenergic blockade licenses the use of immunotherapy in primary brain tumors and brain metastases
Authors: Lorrey Selena , Wachsmuth Lucas , Price Mackenzie , Neff Corey , Ostrom Quinn , Fecci Peter 
Published: March 2024

Abstract
Immunotherapy is less effective against intracranial metastases compared to extracranial metastases and ineffective against primary brain tumors such as glioblastoma. Brain tumors present a unique challenge to in the context of immunotherapy, as these patients are immunosuppressed not just locally at the tumor, but also outside the CNS. Importantly, systemic immunosuppression observed in brain tumor patients limits the capacity of the immune system to respond to immunotherapy. Through this work we present a novel axis of immunosuppression in patients with intracranial tumors and demonstrate that overactive adrenergic signaling is a major barrier to immunotherapeutic success. Our data indicate that combining beta-adrenergic blockade with immunotherapy provides a survival benefit in the setting of brain tumors, where immunotherapy alone has proven ineffective. We demonstrate that this survival benefit is driven by a remodeling of the tumor microenvironment, increasing NF-kB activity and resulting in an increase in cDC1s and CD8+ T cells, as well as an increase in CD40-CD40L signaling, suggesting the immune system is poised to respond to immunotherapy. Further, we demonstrate that beta-adrenergic blockade can overcome systemic immunosuppression to restore the capacity of T cells to respond to an immune stimulus. Using the SEER-Medicaid database, we retrospectively examined outcomes in patients with melanoma and lung adenocarcinoma brain metastasis who received checkpoint blockade therapy alone vs those concurrently receiving beta-blocker therapy. We found that patients receiving combination therapy showed increased overall survival compared to those receiving checkpoint blockade alone. We then validated these findings in preclinical models of glioma, demonstrating that combining immunotherapy and propranolol, a widely prescribed FDA-approved beta-blocker, extended survival. Moving forward, we proffer that combination therapy with beta-blocker and immunotherapy, particularly checkpoint blockade, represents a promising translational treatment platform for patients with primary or metastatic intracranial malignancies.
Citation Format: Selena Lorrey, Lucas Wachsmuth, Mackenzie Price, Corey Neff, Quinn Ostrom, Peter Fecci. Beta-adrenergic blockade licenses the use of immunotherapy in primary brain tumors and brain metastases [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr PR-001.
Abstract A028: Investigating the role of SOX2 in promoting anchorage-independent survival of ovarian cancer cells
Authors: Kamlapurkar Shriya , Stump Coryn , Karthikeyan Mythreye , Hempel Nadine 
Published: March 2024

Abstract
Ovarian cancer (OVCA) is the most lethal gynecologic malignancy, often detected at an advanced stage. OVCA progression involves transcoelomic metastasis, where tumor cells disseminate into the peritoneal ascites. Malignant cells in the ascites adapt to survive under Anchorage-Independent (A-I) conditions by altering the expression of genes escalating anoikis (A-I cell death) resistance and metastasis. Our lab has shown that OVCA cells manipulate their transcriptomic profile to promote the expression of anoikis resistance genes in A-I. Expression profiling of genes upregulated in A-I revealed the transcription factor SRY-Box Transcription Factor 2 (SOX2) to be highly upregulated in response to OVCA cell detachment. While we have previously demonstrated that SOX2 is necessary for the A-I survival of OVCA cells, the specific mechanism underlying SOX2-dependent A-I survival remains unknown. RNA-sequencing studies performed in the high-grade serous ovarian cancer cell line, OVCAR3, revealed that the Leucine-rich repeat-containing G-protein coupled receptor 5, LGR5, is the most significantly upregulated gene in A-I compared to attached conditions. Importantly, amongst those genes that are upregulated in A-I, LGR5 is significantly downregulated following SOX2 knockdown in A-I. LGR5 is an ‘orphan’ G-protein coupled receptor known to modulate canonical Wnt signaling upon interacting with its ligand R-spondin1 (RSPO1). Time-course experiments in OVCAR3 cells revealed a striking increase in LGR5 expression that peaked after 24 hours in A-I. Furthermore, siRNA mediated knockdown of SOX2 downregulated LGR5 expression only in A-I, suggesting that LGR5 is a potential SOX2 target under A-I conditions. Interestingly, bioinformatics analysis of the existing OVCA datasets from the Cancer Genome Atlas showed increased expression of RSPO1, which correlated with a significant decrease in the overall survival of OVCA patients. Interaction of LGR5 with its ligand RSPO1 is crucial for the receptor to signal through the Wnt pathway to promote cell survival and cancer stemness. Although SOX2 and LGR5 are established markers of cancer stemness in various tumor types, their direct relationship in promoting tumor progression and regulation of OVCA A-I cell survival remains unknown. Our data suggests that increased SOX2 and LGR5 expression could drive OVCA cell survival under A-I conditions. Our current studies focus on understanding the molecular mechanisms behind SOX2-driven regulation of LGR5 and the role of LGR5 in driving OVCA A-I cell survival.
Citation Format: Shriya Kamlapurkar, Coryn Stump, Mythreye Karthikeyan, Nadine Hempel. Investigating the role of SOX2 in promoting anchorage-independent survival of ovarian cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A028.
Abstract A048: Utero-tubal lavage proteomic analysis: detection of ovarian cancer in BRCA mutation carriers
Authors: Bahar-Shany Keren , Barnabas Georgina D. , Korach Jacob , Jakobson-Setton Ariella , Geiger Tamar , Levanon Keren 
Published: March 2024

Abstract
No current screening methods for high-grade ovarian cancer (HGOC) guarantee effective early detection for high-risk women such as germline BRCA mutation carriers. Therefore, the standard-of-care remains risk-reducing salpingo-oophorectomy (RRSO) around age 40. Proximal liquid biopsy is a promising source of biomarkers, but sensitivity has not yet qualified for clinical implementation. We aimed to develop a proteomic assay based on proximal liquid biopsy, as a decision support tool for monitoring high-risk population. Ninety Israeli BRCA1 or BRCA2 mutation carriers were included in the training set (17 HGOC patients and 73 asymptomatic women), (BEDOCA trial; ClinicalTrials.gov Identifier: NCT03150121). The proteome of the microvesicle fraction of the samples was profiled by mass spectrometry and a classifier was developed using logistic regression. An independent cohort of 98 BRCA mutation carriers was used for validation. Safety information was collected for all women who opted for uterine lavage in a clinic setting. We present a 7-protein diagnostic signature, with AUC &gt;0.97 and a negative predictive value (NPV) of 100% for detecting HGOC. The AUC of the biomarker in the independent validation set was &gt;0.94 and the NPV &gt;99%. The sampling procedure was clinically acceptable, with favorable pain scores and safety. We conclude that the acquisition of Müllerian tract proximal liquid biopsies in women at high-risk for HGOC and the application of the BRCA-specific diagnostic assay demonstrates high sensitivity, specificity, technical feasibility, and safety. A similar classifier for an average-risk population is warranted.
Citation Format: Keren Bahar-Shany, Georgina D. Barnabas, Jacob Korach, Ariella Jakobson-Setton, Tamar Geiger, Keren Levanon. Utero-tubal lavage proteomic analysis: detection of ovarian cancer in BRCA mutation carriers [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A048.