bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A015: A synergistic combination of a novel mTORC1-activator with proteasome inhibitor confers a remission in acute myeloid leukemia
Authors: Pattanayak Shakti Prasad , Sunita Priyashree , Hajihassani Omid , Fisher-Wellman Kelsey , Wald David , Eriksson Leif A , Tirosh Boaz 
Published: October 2024

Abstract
Despite the well-characterized oncogenic properties of mTORC1, in the presence of chemotherapy or other stress conditions, the suppression of mTORC1 promotes survival and bestows tumors with drug resistance. While highly potent inhibitors of mTORC1 were developed, small molecules that activate mTORC1 directly are lacking. The best way to activate mTORC1 is by suppressing its negative regulator, the tuberous sclerosis complex, which comprises TSC1, TSC2, and TBC1D7. We discovered that, deleting TSC2 upsurged the sensitivity of multiple myeloma cells to proteasome inhibitors (PI s). To replicate this pharmacologically, we designed in silico docking and additional chemical modifications to create AcTor, a potential first-of-its-kind TSC2 inhibitor. When AcTor was used in combination with the proteasome inhibitor ixazomib (IXZ), we identified a significant boost in cytotoxic activity in multiple myeloma cells. The combination had an even stronger effect in various acute myeloid leukemia (AML) cell lines. AcTor and IXZ together led to a rapid loss of mitochondrial activity in AML cells, specifically affecting complex IV of the electron transport chain and generating ROS. In animal models, AcTor alone accelerated AML growth, which aligns with mTORC1 activation. However, when combined with IXZ for three weeks, the growth of AML was inhibited, and the leukemic cells underwent apoptosis. This effect was perceived in both peripheral blast cells and the leukemic stem cells in the bone marrow, which are particularly challenging to eliminate. In a relapse model of AML, the AcTor/IXZ treatment sustained to be effective even after the tumor reoccurred. We suggest that treatment courses with AcTor and IXZ could offer a lasting anti-AML benefit, both before and after relapse.
Citation Format: Shakti Prasad Pattanayak, Priyashree Sunita, Omid Hajihassani, Kelsey Fisher-Wellman, David Wald, Leif A Eriksson, Boaz Tirosh. A synergistic combination of a novel mTORC1-activator with proteasome inhibitor confers a remission in acute myeloid leukemia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A015.
Abstract A032: KRAS mutations have distinct effects on the tumor immune microenvironment in pancreatic cancer
Authors: Wenger Andrew , Baron Tal , Vega-Perez Adrian , Sisso Whitney , Zafra Maria Paz , Dow Lukas , Siolas Despina 
Published: October 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with abysmal survival rates. The highly immunosuppressive microenvironment of PDAC poses a major barrier to effective therapy. KRAS mutations are near-ubiquitous in PDAC, and studies indicate clinical outcomes vary depending on the specific KRAS genotype. Given that tumor genotype can shape the immune cell composition of tumors, we examined the immune cell composition of pancreatic tumors with specific KRAS mutations, focusing on KRASG12D mutations (representing 40% of PDAC cases which have the worst prognosis) and KRASG12R mutations (which make up 20% of PDAC cases and have a better prognosis). Orthotopically implanted Kras G12R/+ ;Trp53 KO mouse pancreatic tumors have a distinct immune profile in comparison to Kras G12D/+ ;Trp53 KO tumors, characterized by an influx of intratumoral CD3+ T cells and mature dendritic cells. Selective depletion of CD4+ T cells induces a rapid progression in KRASG12R, but not KRASG12D mouse tumors. RNA sequencing of KRASG12R tumor cells revealed enrichment of Type I interferon (IFN) pathways accompanied by related chemokines, CXCL9 and CXCL10 in comparison to KRASG12D tumors. Analysis of publicly available human PDAC cohorts revealed enrichment of genes in inflammatory pathways in KRASG12R tumors. Collectively, these data link the KRASG12R mutation to an immunogenic role that is distinct from KRASG12D tumors.
Citation Format: Andrew Wenger, Tal Baron, Adrian Vega-Perez, Whitney Sisso, Maria Paz Zafra, Lukas Dow, Despina Siolas. KRAS mutations have distinct effects on the tumor immune microenvironment in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A032.
Abstract B015: Wnt inhibition improves the efficacy of anti-PD-1 therapy in glioblastoma
Authors: Krishnan Shanmugarajan , Lee Somin , Amoozgar Zohreh , Subudhi Sonu , Kumar Ashwin S. , Posada Jessica , Lindeman Neal , Lei Pinji , Duquette Mark , Huang Peigen , Andersson Patrik , Datta Meenal , Munn Lance L. , Fukumura Dai , Jain Rakesh K. 
Published: October 2024

Abstract
Immune checkpoint blockers, including anti-PD-1 (αPD1), have failed in multiple phase III clinical trials in glioblastoma (GBM), a malignant brain tumor with a median survival of &lt;2 years with current treatments. Wnt signaling plays a crucial role in multiple developmental processes and contributes to limited treatment outcomes of several malignancies, including GBM. Wnt signaling aids GBM progression by maintaining stemness, promoting epithelial-mesenchymal transition, and inducing chemoresistance. Preclinical evidence indicates that Wnt signaling may contribute to αPD1 resistance in extracranial tumors. However, its pertinence in the failure of αPD1 in GBM is unknown. In our study, we identified Wnt7b, upregulated in GBM patients, is a determinant of resistance to αPD1 therapy in a clinically relevant GBM murine model with abundant GSCs. Increased levels of Wnt7b and β-catenin correlated with resistance to αPD1 therapy. We hypothesized that Wnt inhibition could potentiate αPD1 therapy by reprogramming the immunosuppressive tumor microenvironment (TME) to an immune-stimulatory state. We orthotopically implanted a stem-rich syngeneic mouse GBM cell line, GSC005, into immunocompetent mice, then tracked tumor growth and analyzed tumor and immune cell subpopulations using Western blot, qPCR, and immunohistochemistry and flow cytometry. Combining a porcupine inhibitor (WNT974) with αPD1 therapy enhanced anti-tumor immune responses and extended the median survival of mice with orthotopic GBM from 25 to 59 days, with 25% cured. Furthermore, this combination reprogrammed the TME, increasing antigen-presenting DC3-like dendritic cells and reducing granulocytic myeloid-derived suppressor cells (gMDSCs). Moreover, it increased the Ki67+CD8/Ki67+Treg (regulatory T cell) ratio, shifting the CD8 balance towards an anti-tumor immune response. Interestingly, resistance to the combination therapy was associated with an increase in monocytic MDSCs (mMDSCs). Our preclinical findings provide compelling data and rationale to test WNT974, reported to be safe in a Phase I trial in extracranial cancer patients, in combination with αPD1 therapy in GBM patients with elevated Wnt7b/β-catenin signaling.
Citation Format: Shanmugarajan Krishnan, Somin Lee, Zohreh Amoozgar, Sonu Subudhi, Ashwin S. Kumar, Jessica Posada, Neal Lindeman, Pinji Lei, Mark Duquette, Peigen Huang, Patrik Andersson, Meenal Datta, Lance L. Munn, Dai Fukumura, Rakesh K. Jain. Wnt inhibition improves the efficacy of anti-PD-1 therapy in glioblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B015.
Abstract B024: Causal Association between Wnt/β-catenin Gene expression with Cervical Cancer Risk: Two Sample Mendelian Randomization (MR)
Authors: Jee Yongho , Ju Woong 
Published: October 2024

Abstract
Background: Increasing evidence indicates that Wnt/β-catenin signaling, one of the best-characterized cancer drivers, promotes cancer progression by regulating the tumor-immune cycle. This study aims to test this hypothesis using Mendelian Randomization (MR), which can infer causality free from confounding factors. Methods: We utilized the Icelandic deCODE Genetics dataset (deCODE), published by Ferkingstad et al. (2021), which analyzes genetic variations, plasma proteins, and diseases in a cohort of 35,559 Icelandic individuals. Additionally, we used the Biobank Japan (BBJ) dataset, a large-scale biobank comprising genetic and biomarker information from approximately 200,000 Japanese individuals. Genetic variations related to the protein quantitative trait loci (pQTL) for Wnt/β-catenin genes (specifically WNT10A) were identified in the deCODE dataset. Corresponding SNPs associated with cervical cancer risk were identified in the BBJ dataset. We examined the pQTL-related single nucleotide polymorphisms (SNPs) of Wnt/β-catenin genes. Two-sample MR was performed to infer causality between Wnt/β-catenin pQTL expression levels and cervical cancer risk using the SNPs identified in the BBJ biobank. Results Before removing outliers, the analysis included 9 SNPs related to the pQTL expression of WNT10A. Using inverse variance weighting, the odds ratio (OR) was calculated as 1.19 (0.71-2.00, 95% confidence interval, p-value: 0.5044), indicating no statistically significant causality. After removing duplicated SNPs and conducting Linkage Disequilibrium (LD) clumping, 7 SNPs were included in the final analysis. The effect of WNT10A on cervical cancer was recalculated using inverse variance weighting, yielding an OR of 1.21 (0.79-1.84, 95% confidence interval, p-value: 0.3767), still indicating no statistically significant causality. Conclusions This study highlights the application of MR, which is robust against confounding variables, to explore the causal association between Wnt/β-catenin pQTL expression and cervical cancer risk. While our results do not support a significant causal relationship, the use of MR provides valuable insights and has public health implications for discovering new drug targets or biomarkers for prevention or treatment.
Citation Format: Yongho Jee, Woong Ju. Causal Association between Wnt/β-catenin Gene expression with Cervical Cancer Risk: Two Sample Mendelian Randomization (MR) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B024.
Abstract B039: Elucidating the tumor-driven mechanisms of resistance to immunotherapies in pancreatic cancer through in vivo CRISPR/Cas9 knockout screening
Authors: Froese Julia , Whittaker Charlie , Leclerc Paul , Langenbucher Adam , Hellinger Riley , Goulet Daniel , Hemann Michael T. 
Published: October 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer death by 2030. PDAC lacks effective treatment options and innovative strategies for therapeutic intervention are urgently needed. Chimeric Antigen Receptor (CAR)-T cell therapy has shown remarkable success in treating hematologic malignancies, yet achieving efficacy in solid tumors remains a significant challenge. Early results from clinical trials show limited efficacy of CAR T-cell therapy in PDAC. To uncover tumor-intrinsic mechanisms of resistance to CAR T-cell therapy in vivo, we performed iterative CRISPR/Cas9-based pooled screens in a fully immunocompetent, orthotopic model of PDAC. We identified a variety of genes influencing CAR T-cell treatment efficacy. In particular, loss of genes involved in redox biology and oxidative stress sensitized PDAC tumors to CAR T-cell therapy in vivo. Additionally, single-cell RNA sequencing of PDAC tumors subjected to CAR T-cell therapy unveiled a distinct subset of tumor cells resilient to the treatment, characterized by changes in oxidative stress. Our findings indicate a potential avenue for therapeutic synergy by targeting pathways involved in oxidative stress to increase the efficacy of CAR T cell therapy in PDAC.
Citation Format: Julia Froese, Charlie Whittaker, Paul Leclerc, Adam Langenbucher, Riley Hellinger, Daniel Goulet, Michael T. Hemann. Elucidating the tumor-driven mechanisms of resistance to immunotherapies in pancreatic cancer through in vivo CRISPR/Cas9 knockout screening [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B039.
Abstract B052: Recombinant Listeria-Monocytogenes Vaccine Induces Anti-tumor Immune Response in Inflammatory Cell Death Machinery-Deficient Mice
Authors: Olagunju Abolaji S , Victor Sardinha Andrew Diniz , Amarante-Mendes Gustavo P. 
Published: October 2024

Abstract
Recombinant Listeria monocytogenes (LM)-based cancer vaccines show an optimistic immunotherapeutic approach for treating cancer. Employing LM's unique capacity to stimulate strong and targeted anticancer immune responses and activation of in vivo antigen-specific CD8+ T cells. LM has been shown to trigger inflammatory and/or immunogenic cell death processes, including necroptosis and pyroptosis, to modulate immunological responses positively. Nevertheless, the consequence of the deficiency of the host inflammatory cell death machinery on the efficacy of LM to induce an effective anti-tumor immune response remains unresolved. Therefore, we projected that a deficiency in regulatory or effector molecules involved in necroptosis or pyroptosis would interfere with the host response to LM and the consequent stimulation of CD8+ T cell-mediated immunity. To test our hypothesis, wild-type (WT), caspase-1/11-/-, gsdmd-/-, ripk3-/-, and mlkl-/-C57Bl/6 mice were vaccinated with recombinant L. monocytogenes carrying the ovalbumin gene (LM.OVA) intravenously. An in vivo cytotoxicity assay was carried out to assess the efficiency of target cell elimination by OVA-specific CD8+ T lymphocytes. In addition, the in vivo growth of B16F0 and B16F0.OVA melanoma cell lines were measured in control and vaccinated mice. Our findings showed that Caspase-1/11 and GSDMD help control LM-OVA infection, but a single deficiency of either of the molecules did not affect the LM-OVA-induced antigen-specific anti-tumor response.
Citation Format: Abolaji S Olagunju, Andrew Diniz Victor Sardinha, Gustavo P. Amarante-Mendes. Recombinant Listeria-Monocytogenes Vaccine Induces Anti-tumor Immune Response in Inflammatory Cell Death Machinery-Deficient Mice [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B052.
TCIC-SC-RNet: A Hybrid Model for TC Intensity Estimation Based on Transfer Learning
Authors: Zhang Chang-Jiang , Wang Yu , Ma Lei-Ming , Lu Xiao-Qin 
Published: October 2024

Abstract
Tropical cyclone (TC) monitoring relies heavily on remotely sensed observations as they generally form and move through remote oceanic areas. This is an important part of monitoring the TC current intensity. In this study, a hybrid model (TCIC-SC-RNet) based on transfer learning, consisting of a cascade of classification, secondary correction classification, and regression modules, is proposed to estimate the intensity of TCs in the northwest Pacific basin. We used 1023 TCs (1979, 1981–2019), totaling 23 629 infrared satellite images, to train and test the TCIC-SC-RNet model. First, an improved Swin Transformer network is used to divide TCs into three categories according to intensity levels. Then, the primary classification result combines with direct intensity estimation results of the RegNet model input into the secondary correction classification module to classify further TCs, so as to reduce the misclassification errors and improve the model effect. Finally, the corrected TC intensity classification results are sent to the corresponding RegNet regression network to output the estimated TC intensity. The results show that the total root-mean-square error (RMSE) and mean absolute error (MAE) of our model were 7.47 and 5.60 kt (1 kt ≈ 0.51 m s−1), respectively, compared with the TC best track, which is competitive among current TC intensity estimation models.
Prostate cancer cell-derived exosomes ZNF667-AS1 reduces TGFBR1 mRNA stability to inhibit Treg expansion and DTX resistance by binding to U2AF1
Authors: Shi Zhenfeng , Pu Wenjing , Li Min , Aihemaitijiang Mierzhayiti , Li Shuo , Zhang Xiaoan , Liu Bide , Sun Min , Li Jiuzhi , Li Zhiwei 
Published: October 2024

Abstract
Background
Docetaxel (DTX) resistance attenuates anti-tumor effects of DTX on prostate cancer (mCRPC) and drug resistance was related to Treg expansion in tumors. ZNF667-AS1 played a suppressing role in various tumors and tumor-derived exosomes carry lncRNAs to participate in tumor progression. Here, the effects of ZNF667-AS1 on malignant characteristics and DTX resistance in PC and the effect and its underlying molecular mechanism of tumor-derived exosomes carrying ZNF667-AS1 on Treg expansion were investigated.

Methods
The identification of exosomes were determined using TEM, NTA and western blot. The abundance of genes and proteins were evaluated using IHC, RT-qPCR, western blot and FISH. Malignant phenotypes of PC cells were evaluated by means of Edu, scratch test, transwell, CCK-8 and flow cytometry. The percentage of CD4+CD25+Foxp3+ Tregs was detected using flow cytometry. The location of ZNF667-AS1 was detected using nuclear-cytoplasmic fractionation. The co-location of ZNF667-AS1 and U2AF1 protein was detected using IF-FISH assay. The interactions among ZNF667-AS1, TGFBR1 and U2AF1 were verified using RNA pull-down, RIP and dual luciferase activity.

Results
ZNF667-AS1 expression in PC samples was lowered, which was negatively relative to poor prognosis and DTX resistance. ZNF667-AS1 overexpression inhibited malignant phenotypes of PC cells, tumor growth and DTX resistance. Besides, DTX resistant cell-derived exosomes expressed lower ZNF667-AS1 expression. Exosomes carrying exogenously high ZNF667-AS1 expression derived PC cells or serum of mice suppressed Treg expansion. On the mechanism, ZNF667-AS1 interacted with U2AF1 to destabilize TGFBR1 mRNA and reduce TGFBR1 expression in CD4+T cells.

Conclusion
ZNF667-AS1 suppressed cell growth of PC cells, tumor growth of mice and DTX resistance to PC cells and exogenously high ZNF667-AS1 expression in tumor-derived exosomes destabilized TGFBR1 mRNA and reduce TGFBR1 expression through interacting with U2AF1, thus resulting in attenuated Treg expansion, which was related to DTX resistance.
Application of the estimand framework for an emulated trial using reference based multiple imputation to investigate informative censoring
Authors: Atkinson A. , Zwahlen M. , De Wit S. , Furrer H. , Carpenter J. R. 
Published: October 2024

Abstract
Background
The ICH E9 (R1) addendum on Estimands and Sensitivity analysis in Clinical trials proposes a framework for the design and analysis of clinical trials aimed at improving clarity around the definition of the targeted treatment effect (the estimand) of a study.

Methods
We adopt the estimand framework in the context of a study using “trial emulation” to estimate the risk of pneumocystis pneumonia, an opportunistic disease contracted by people living with HIV and AIDS having a weakened immune system, when considering two antibiotic treatment regimes for stopping antibiotic prophylaxis treatment against this disease. A “while on treatment” strategy has been implemented for post-randomisation (intercurrent) events. We then perform a sensitivity analysis using reference based multiple imputation to model a scenario in which patients lost to follow-up stop taking prophylaxis.

Results
The primary analysis indicated a protective effect for the new regime which used viral suppression as prophylaxis stopping criteria (hazard ratio (HR) 0.78, 95% confidence interval [0.69, 0.89], p < 0.001). For the sensitivity analysis, when we apply the “jump to off prophylaxis” approach, the hazard ratio is almost the same compared to that from the primary analysis (HR 0.80 [0.69, 0.95], p = 0.009). The sensitivity analysis confirmed that the new regime exhibits a clear improvement over the existing guidelines for PcP prophylaxis when those lost to follow-up “jump to off prophylaxis”.

Conclusions
Our application using reference based multiple imputation demonstrates the method’s flexibility and simplicity for sensitivity analyses in the context of the estimand framework for (emulated) trials.
An investigation of the impact of ‘Living with COVID’ on workplace COVID-19 transmission risk, response and resilience - lessons learnt and future challenges
Authors: Lewis Catherine , Johnson Sheena , Mann Claire , Ubido Janet , Farrell Bernadine , Coleman Anna , van Tongeren Martie 
Published: October 2024

Abstract
Background
Previous research has highlighted links between occupation and risk of COVID-19 transmission and suggests that occupational risk is influenced by covariates including socio-economic status, and deprivation. This study examined the perspectives of local authority teams of how changes in policy and advice, as set out in the UK government report ‘Living with COVID,’ affected COVID-19 transmission risk, response and resilience in workplace settings in Greater Manchester, an area that was disproportionately affected by the pandemic.

Methods
The project, which took place between August and November 2022, undertook a mixed methods approach to incorporate wide-ranging reflections of changes following the publication of ‘Living with COVID’. Quantitative data was collected from local employers (n = 149) and employees (n = 397) using online surveys, and qualitative interview data was collected from Greater Manchester local authority teams (n = 19).

Results
The research highlighted the inequitable impact of the pandemic on those already experiencing health inequalities, including people on more precarious employment contracts or those who were unable to work from home during the pandemic.
The study found that the facilitators that helped local authorities to support employers to manage transmission included clear, detailed and timely national and local guidance, good communication, partnership working, funding, and timely access to data. Barriers to supporting employers included contradictory or confusing national guidance, structural inequalities, lack of funding, and delayed access to data. Interview participants reported that they were now utilising lessons learnt during the pandemic, along with the that partnerships developed, in order to tackle wider health issues and to prepare for future pandemics or health crises.

Conclusion
The findings of the study, which concur with previously published research conducted as part of the PROTECT project, highlight the importance of active reflection on the lessons learned during the course of the pandemic. The study draws on PH and EH teams’ perspectives of managing COVID-19 transmission, in an area that was disproportionately affected by the pandemic, in order to add to our understanding of the best ways to ensure preparedness for future pandemics or health crises at a national level.