bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spinor walls in five-dimensional warped spacetime
Authors: Cui Zheng-Quan , Liu Yu-Xiao 
Published: April 2023

AbstractWe study domain wall solutions of a real spinor field coupling with gravitation in five dimensions. We find that the nonlinear spinor field supports a class of soliton configurations which could be viewed as a wall embedded in five dimensions. We begin with an illuminating solution of the spinor field in the absence of gravitation. In a further investigation, we exhibit three sets of solutions of the spinor field with nonconstant curvature bulk spacetimes and three sets of solutions corresponding to three constant curvature bulk spacetimes. We demonstrate that some of these solutions in specific conditions have the energy density distributions of domain walls for the spinor field, where the scalar curvature is regular everywhere. Therefore, the configurations of these walls can be interpreted as spinor walls which are interesting spinor field realizations of domain walls. In order to investigate the stability of these spinor configurations, the linear perturbations are considered. The localization of the zero mode of tensor perturbation is also discussed.
Comparison of Efficacy and Safety of Different Doses of Dexmedetomidine for Epidural Labor Analgesia
Authors: Ge Liang , Zhang Peng , Kong Lingguo , Wang Wei , Tong Qian , Fan Quanlong , Han Xudong 
Published: April 2023

Objective. To explore the efficacy and safety of different doses of dexmedetomidine (DEX) for epidural labor analgesia (ELA). Methods. From June 2021 to June 2022, 147 parturients who underwent ELA in our hospital were selected and divided into low- (0.5 μg/kg DEX), medium- (0.75 μg/kg DEX), and high-dose (1.0 μg/kg DEX) groups (n = 49 for each) according to the random number table method. The analgesic effect was assessed using the Ramsay sedation score and Visual Analogue Scale (VAS), and the labor duration, mean arterial pressure (MAP), and heart rate (HR) before and after analgesia, vaginal bleeding within 2 h postpartum, and delivery outcomes (the cesarean section conversion rate and the neonatal Apgar score) were statistically analyzed. Furthermore, the incidence of adverse reactions was calculated, and maternal satisfaction with delivery was investigated. Results. After analgesia, the the Ramsay and labor duration were higher in the high-dose group than those in the low- and medium-dose groups, and the VAS scores was lowerin the high-dose group than those in the low- and medium-dose groups

P
<
0.05

, while no difference was identified among the three groups in terms of the cesarean section conversion rate and the neonatal Apgar score

P
>
0.05

. The high-dose group had the greatest fluctuations in MAP and HR levels before and after analgesia than the other two groups, with a higher incidence of adverse reactions

P
<
0.05

. Finally, the survey of delivery satisfaction showed no significant difference in delivery satisfaction among the three groups

P
>
0.05

. Conclusion. DEX has excellent performance in ELA, which can effectively relieve the pain of puerperae and shorten the labor process. Among them, low-dose DEX has higher safety and is recommended as the first choice. Trial Registrations. This trial is registered with ML2021073.
Abstract 1283: MUC5AC promotes brain metastases and colonization in non small cell lung cancer
Authors: Chaudhary Sanjib , Maurya Shailendra Kumar , Siddiqui Jawed , Nasser Mohd W. , Batra Surinder K. , Lakshmanan Imayavaramban , Ganti Apar Kishor 
Published: April 2023

Abstract
Background: Non-small cell lung adenocarcinoma (NSCLC), constitutes 80-85% of the lung cancers. The 5-year survival of patients with metastatic lung cancer is only 5%. Additionally, the prognosis worsens in NSCLC patients (40-50%) that have developed brain metastasis. Mucin 5AC (MUC5AC) is overexpressed in the primary NSCLC and brain metastatic tissues; however, the mechanism in the MUC5AC-mediated brain metastasis is unclear.
Methods: Immunohistochemistry was performed on lung cancer samples. Expression studies were conducted in the brain-tropic cell lines (A549-BrM, PC9-BrM, and HCC4006-BrM cells) and their respective parental lines. CRISPR Cas9 or shRNA was used to either knockout/knockdown MUC5AC in the cell lines. Mass-spectrometry analysis and protein arrays were conducted in the brain trophic cells. In vivo mouse models involving intracardiac injection of cancer cells were performed, and the effect of MUC5AC brain metastasis and survival was analyzed.
Results: MUC5AC was significantly increased in NSCLC brain metastatic tissues. Similarly, MUC5AC expression was elevated in NSCLC brain tropic (BrM) cell lines compared to parental lines. Treatment of BrM or parental cells with the conditioned media of normal human astrocytes resulted in increased MUC5AC levels. We observed astrocyte-derived CCL2-induced the MUC5AC expression in both parental and BrM cells. Mass-spectrometry based proteomic analysis indicated decreased cell adhesion molecules such as ALCAM, ITGB4, ITGB5, CDH17, and DSG2 in MUC5AC knockdown tropic cells. Further, Mass-spectrometry based interactome studies revealed MUC5AC interaction with Annexin A2 enabling the cancer cell adhesion. Intracardiac injection of MUC5AC knockdown A549-BrM (A549-BrM-shMUC5AC) cells showed a significant reduction in brain metastasis and increased survival of the mice compared to scramble control group (P&lt;0.001).
Conclusion: Our study identified the role of MUC5AC in metastasis and colonization in the brain environment. Mechanistically, MUC5AC interacts with the Annexin A2 during metastasis, while astrocyte derived CCL2 further induced the MUC5AC expression facilitating the colonization of the NSCLC cells in the brain. Hence, targeting MUC5AC and its interactions partner Annexin A2 may prevent NSCLC brain metastasis.
Citation Format: Sanjib Chaudhary, Shailendra Kumar Maurya, Jawed Siddiqui, Mohd W. Nasser, Surinder K. Batra, Imayavaramban Lakshmanan, Apar Kishor Ganti. MUC5AC promotes brain metastases and colonization in non small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1283.
Abstract 1581: KSQ-4279, a first-in-class USP1 inhibitor shows strong combination activity with multiple PARP inhibitors in BRCA mutant cancers
Authors: Tobin Erica , Sullivan Pamela , Murray Morgan , Gannon Hugh , Dodson Anne , Shenker Sol , Stegmeier Frank , Wylie Andrew , Cadzow Louise 
Published: April 2023

Abstract
Tumors harboring BRCA1/2 mutations and other homologous recombination deficiencies are sensitive to agents targeting pathways involved in DNA repair including poly (ADP-ribose) polymerase (PARP) inhibitors, which have been approved for the treatment of BRCA mutant cancers. Despite the clinical benefit with these drugs, many patients achieve incomplete disease control and often develop resistance. By employing our CRISPRomics® technology to screen over 600 cancer cell lines, we identified the deubiquitinating enzyme USP1 as one of the top targets that displays selective anti-tumor activity in ovarian and triple negative breast cancers with homologous recombination deficiencies. Subsequent drug discovery efforts identified KSQ-4279 as a potent and highly selective first-in-class small molecule USP1 inhibitor that is now in clinical development. In preclinical models, we previously demonstrated that KSQ-4279 shows therapeutic potential in combination with olaparib for treating patients who are either intrinsically resistant, or have developed acquired resistance to PARP inhibitors. We performed studies to investigate the therapeutic potential of combining KSQ-4279 across a variety of PARP inhibitors with different ‘PARP trapping’ potencies. Clonogenic assays demonstrated synergistic effects of KSQ-4279 across multiple PARP inhibitors regardless of their PARP trapping potency. Second generation PARP1 selective inhibitors such as AZD5305 are currently in clinical development and may provide a safety and efficacy advantage for patients. We have investigated the potential of combining KSQ-4279 with AZD5305 in a PARP refractory patient-derived triple negative breast cancer (TNBC) xenograft model by evaluating tolerability and anti-tumor efficacy. We observed significantly greater and more durable anti-tumor activity, including regressions, with the combination therapy compared to single agents. Our data supports the clinical testing of KSQ-4279 in combination with PARP inhibitors.
Citation Format: Erica Tobin, Pamela Sullivan, Morgan Murray, Hugh Gannon, Anne Dodson, Sol Shenker, Frank Stegmeier, Andrew Wylie, Louise Cadzow. KSQ-4279, a first-in-class USP1 inhibitor shows strong combination activity with multiple PARP inhibitors in BRCA mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1581.
Abstract 1673: Discovery of potent, selective, and orally bioavailable GSPT1 degraders and their pre-clinical anti-tumor activity in acute myeloid leukemia and solid tumors
Authors: Joo Min Sung , Lee JaeYung , Kim Eun-Jung , Ki Dong Hyuk , Choi Hunmi , Nam Joonwoo , Park Jaewoo , Kang Keon Wook , Han Wooseok 
Published: April 2023

Abstract
Molecular glue degraders (MGDs) of neo-substrates that function by hijacking the CRBN E3 ligase are clinically validated as therapeutics for the treatment of hematological malignancies. Novel MGDs of GSPT1, a translation termination factor, elicit dysregulated protein translation termination and subsequent induction of TP53-independent apoptosis in acute myeloid leukemia (AML) cells through activation of the integrated stress response. In addition, dysregulation of translation termination triggered by GSPT1 degradation appears to be cytotoxic specifically to MYC-driven cancers including solid tumors with translational addiction. Phase 1 clinical trials of three novel GSPT1 MGDs have been recently launched for the treatment of AML and/or MYC-driven solid tumors (NCT02848001, NCT04336982, NCT05546268, and NCT05144334). Herein, we present novel GSPT1 MGDs and their pre-clinical results against AML and solid tumors. Our current lead GSPT1 MGDs induced rapid, potent, and durable degradation of GSPT1, resulting in strong inhibition of tumor cell growth in a variety of cell lines of MYC-driven solid tumor and blood cancer (AML and acute lymphoblastic leukemia). Moreover, in ex-vivo assays using a panel of patient-derived primary AML cells, C-10386 was highly sensitive with EC50s at the nanomolar range. Furthermore, a related analogue (C-14207) showed excellent rodent PK profiles and demonstrated dose-dependent PKPD relationship and excellent efficacy in the NCI-H1155 NSCLC xenograft model. Finally, our current lead compounds showed safer profiles in various normal cells compared to other known GSPT1 degraders. Collectively, we have identified novel GSPT1 MGDs as promising development candidates for the treatment of AML and solid tumors.
Citation Format: Min Sung Joo, JaeYung Lee, Eun-Jung Kim, Dong Hyuk Ki, Hunmi Choi, Joonwoo Nam, Jaewoo Park, Keon Wook Kang, Wooseok Han. Discovery of potent, selective, and orally bioavailable GSPT1 degraders and their pre-clinical anti-tumor activity in acute myeloid leukemia and solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1673.
Abstract 1741: Inhibition of pcsk9 impairs the development of vessel co-option and potentiates anti-angiogenic therapy in colorectal cancer liver metastases
Authors: Rada Miran , Krzywon Lucyna , Kapelanski-Lamoureux Audrey , Petrillo Stephanie , Reynolds Andrew , Lazaris Anthoula , Seidah Nabil , Metrakos Peter 
Published: April 2023

Abstract
Colorectal cancer liver metastatic (CRCLM) tumours present as two main histopathological growth patterns (HGPs) including desmoplastic HGP (DHGP) and replacement HGP (RHGP). The DHGP tumours obtain their blood supply by sprouting angiogenesis, whereas the RHGP tumours utilize an alternative vascularisation known as vessel co-option. In vessel co-option, the cancer cells hijack the mature sinusoidal vessels to obtain blood supply. Vessel co-option has been reported as an acquired mechanism of resistance to anti-angiogenic treatment in CRCLM. Herein, we show the connection between serum cholesterol concentration and vessel co-option development in CRCLM. Our clinical data suggested that the elevation of serum cholesterol levels correlates with the risk of developing vessel co-opting tumours. Moreover, inhibition of PCSK9, the key modulator of cholesterol metabolism, significantly attenuated the development of vessel co-opting CRCLM tumours and sensitized the tumours to anti-angiogenic therapy in vivo. Altogether, these data suggest the importance of cholesterol in the development of vessel co-option tumours and propose that inhibiting PCSK9 is a promising strategy to overcome resistance to anti-angiogenic therapy in CRCLM.
Citation Format: Miran Rada, Lucyna Krzywon, Audrey Kapelanski-Lamoureux, Stephanie Petrillo, Andrew Reynolds, Anthoula Lazaris, Nabil Seidah, Peter Metrakos. Inhibition of pcsk9 impairs the development of vessel co-option and potentiates anti-angiogenic therapy in colorectal cancer liver metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1741.
Abstract 1877: Tripokin: potential best-in-class for tumor targeted interleukin-2 (IL2) potentiated by tumor necrosis factor (TNF)
Authors: Prodi Eleonora , Corbellari Riccardo , Matasci Mattia , Neri Dario , De Luca Roberto 
Published: April 2023

Abstract
Among the different pharmacological approaches for cancer treatment, antibody-cytokine fusion proteins (also called “immunocytokines”) represent an emerging class of biopharmaceutical products, capable of boosting the immune system to attack tumor cells as a result of a selective accumulation of pro-inflammatory molecules at the site of disease. When used as single agents, immunocytokines are often not able to cure mice and patients. However, it has been shown by our group that the combination of IL2- and TNF- based products was able to completely eradicate tumors in mouse models and to induce complete responses in cancer patients. We have previously described a novel class of immunocytokine products, termed “potency-matched dual cytokine antibody fusion proteins”, consisting of a tumor-targeting antibody (the F8 antibody, specific to the alternatively spliced EDA domain of fibronectin), simultaneously fused to both IL2 and TNF. To match biological activity of the two payloads a single-point mutation was inserted in the TNF sequence and the resulting product, named IL2-F8-TNFmut was able to selectively localize to tumors with excellent tumor-to-organ ratios and it was found to completely eradicate soft-tissue sarcomas in immunocompetent mice, which did not respond to standard chemotherapy. Moreover, the immunocytokine was able to induce complete responses in a variety of mouse models of cancer. The therapeutic activity was further improved when IL2-F8-TNFmut was used in combination with immune checkpoint inhibitors. At the mechanistic level we observed that the anticancer activity was completely abrogated when CD4+ and CD8+ T cells were depleted, while the contribution of NK cells was negligible. We now report the generation of a new potency-matched dual cytokine antibody fusion protein, named Tripokin based on the L19 antibody, specific to the alternatively spliced EDB domain of fibronectin. Compared to the previous product, Tripokin showed a favorable pharmacokinetic profile in monkey, an excellent localization to neoplastic lesions in mice and was easier to formulate for further clinical applications. When tested in tumor bearing mice, Tripokin revealed a superior anti-cancer activity compared to other IL2-based products.The results obtained in this work provided a rationale for future clinical translation activities using Tripokin as potential best-in-class tumor targeted IL2 product.
Citation Format: Eleonora Prodi, Riccardo Corbellari, Mattia Matasci, Dario Neri, Roberto De Luca. Tripokin: potential best-in-class for tumor targeted interleukin-2 (IL2) potentiated by tumor necrosis factor (TNF) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1877.
Abstract 2272: Targeting the chaperone Hsp90 to activate the immune system and eradicate the triple negative breast cancer
Authors: Eisa Nada , Crowley Vincent M. , Elahi Asif , Kommalapati Vamsi K. , Korkaya Hasan , Debbab Abdessamad , Blagg Brian , Chadli Ahmed 
Published: April 2023

Abstract
Low response rates and immune-related adverse events limit the impact of cancer immunotherapy. To improve clinical outcomes, preclinical studies have shown that combining immunotherapies with N-terminal Hsp90 inhibitors resulted in improved efficacy, even though induction of an extensive heat shock response (HSR) with these inhibitors limited their clinical efficacy as monotherapies. We discovered that Enniatin A (EnnA) binds to the interface between the middle domains of the Hsp90 dimer and destabilizes Hsp90 client oncoproteins without inducing an HSR. EnnA induces cancer cell immunogenic cell death in aggressive breast cancer models and exhibits superior anti-tumor activity compared to Hsp90 N-terminal inhibitors. EnnA reprograms the tumor microenvironment in syngeneic mouse models to promote CD8+ T cell-dependent anti-tumor activity mediated through a reduced level of PD-L1 and activation of CX3CR1 pathway. We propose that EnnA is a promising anti-tumor agent with a mechanism of action involving immunogenic cancer cell toxicity and mobilization of CD8+ T cells into the tumor site.
Citation Format: Nada Eisa, Vincent M. Crowley, Asif Elahi, Vamsi K. Kommalapati, Hasan Korkaya, Abdessamad Debbab, Brian Blagg, Ahmed Chadli. Targeting the chaperone Hsp90 to activate the immune system and eradicate the triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2272.
Abstract 2637: Novel folate receptor alpha-directed antibody-drug conjugate PRO1184 demonstrates broad antitumor activity with a promising safety profile in preclinical models
Authors: Wang Lei , Liu Haidong , Zhou Chang , Han Tae , Zhao Baiteng , Chen Zhu 
Published: April 2023

Abstract
Folate receptor α (FRα) is overexpressed in a range of solid tumors with limited expression in normal tissues, hence an attractive target for an antibody-drug conjugate (ADC). PRO1184 is comprised of a human monoclonal antibody that selectively binds FRα, a novel cleavable hydrophilic linker, and a topoisomerase 1 inhibitor payload, exatecan. Previous studies established that a) PRO1184 exerts potent antitumor activity in cell-derived xenograft (CDX) models representing ovarian, non-small cell lung, and breast cancer, b) with pharmacokinetics (PK) akin to that of the unconjugated parent antibody in rats, and c) with a preliminary safety profile that was more favorable than a DXd-based ADC in cynomolgus monkeys. Further characterization of the activity and safety of PRO1184 is reported here. PRO1184 displays strong binding affinity, rapid internalization, and potent cytotoxicity with the HCC1954 (breast cancer), JEG-3 (choriocarcinoma), and HEC-1-A (endometrial cancer) cells, in vitro. PRO1184 at a single dose of 5 mg/kg produced marked tumor growth inhibition in CDX models with all three cell lines. In 14 patient-derived xenograft (PDX) models encompassing ovarian, gastric, breast, and non-small cell lung cancer, PRO1184 at a single dose of 5 mg/kg elicited robust antitumor activity in all four tumor types, with ORR and CR accomplished in 10 and 3 out of the 14 models, respectively. Antitumor activity was observed in xenografts with both high and low FRα expression, suggesting that PRO1184 may benefit patients with a wide range of FRα expression. Two DM4-based benchmarking ADCs produced modest to negligible tumor growth inhibition in head-to-head comparisons in the CDX and PDX studies. In a GLP cynomolgus monkey toxicity study for PRO1184, main treatment-related findings were consistent with those associated with exatecan and included reversible gastrointestinal and hematologic toxicities. There were no toxicity findings in lungs, which may translate to a lower risk of interstitial lung disease (ILD) compared to DXd-based ADCs in the clinic. In summary, PRO1184 is a promising development candidate for the treatment of FRα-expressing solid tumors. A first in human phase 1/2 study in patients with advanced solid tumors is currently recruiting (NCT 05579366).
Citation Format: Lei Wang, Haidong Liu, Chang Zhou, Tae Han, Baiteng Zhao, Zhu Chen. Novel folate receptor alpha-directed antibody-drug conjugate PRO1184 demonstrates broad antitumor activity with a promising safety profile in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2637.