bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1124: PTEN loss confers resistance to anti-PD-1 therapy in NSCLC by increasing tumor infiltration of T regulatory cells
Authors: Exposito Francisco , Redrado Miriam , Houry Maeva , Hastings Katherine , Molero-Abraham Magdalena , Lozano Teresa , Solorzano Jose L. , Ortega Julian Sanz , Andradas Vera , Amat Ramon , Redin Esther , Leon Sergio , Legarra Naroa , García Javier , Serrano Diego , Valencia Karmele , Robles-Oteiza Camila , Foggetti Giorgia , Felip Enriqueta , Lasarte Juan J. , Paz-Ares Luis , Zugazagoitia Jon , Politi Katerina , Montuenga Luis M , Calvo Alfonso 
Published: June 2023

Abstract
Immune checkpoint inhibitors (ICIs) targeting PD-L1/PD-1 have dramatically improved the management of NSCLC patients. Nevertheless, more than 50% patients will present primary resistance or will develop secondary resistance within 12-25 months after treatment initiation. The mechanisms of resistance to ICIs may depend on tumor-intrinsic molecular/genetic alterations that generate an immunosuppressive tumor microenvironment (isTME). Using In silico analyses (TCGA and AACR-GENIE cohorts), and protein expression analysis in our institutional CIMA-CUN cohort, we have shown that &gt;50% LUSC and ~28% LUAD tumors exhibited reduced PTEN mRNA/protein levels. Patients with PTEN-low tumors had higher levels of CXCL10, PD-L1 and PD-L2. In a cohort of stage IV NSCLC patients treated with ICIs, we found that patients with low tumor PTEN levels were significantly associated with worse OS (p=0.021). We have developed and characterized a Pten-null LUSC model using UN680 cells, which was also refractory to anti-PD-1 when implanted in syngeneic mice. Pten loss led to a deregulation of multiple pathways related to immunosuppression, with a positive enrichment in “IL-6/JAK/STAT3” and “TNF-α via NFkB” hallmarks, identified by GSEA. Tumors from the Pten-null LUSC model were highly metastatic and fibrotic, and secreted TGF-β/CXCL10, thus favoring conversion of CD4+ lymphocytes into Tregs. Human/mouse PTEN-low tumors were enriched in Tregs and immunosuppressive genes. Importantly, treatment of mice bearing Pten-null tumors with TLR agonists+anti-TGF-β, aimed to alter this isTME, led to tumor rejection and immunological memory in 100% of mice. Our results demonstrate that lack of PTEN causes immunotherapy resistance in LUSC by establishing an isTME that can be reversed therapeutically.
Citation Format: Francisco Exposito, Miriam Redrado, Maeva Houry, Katherine Hastings, Magdalena Molero-Abraham, Teresa Lozano, Jose L. Solorzano, Julian Sanz Ortega, Vera Andradas, Ramon Amat, Esther Redin, Sergio Leon, Naroa Legarra, Javier García, Diego Serrano, Karmele Valencia, Camila Robles-Oteiza, Giorgia Foggetti, Enriqueta Felip, Juan J. Lasarte, Luis Paz-Ares, Jon Zugazagoitia, Katerina Politi, Luis M Montuenga, Alfonso Calvo. PTEN loss confers resistance to anti-PD-1 therapy in NSCLC by increasing tumor infiltration of T regulatory cells [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 1124.
Abstract 1329: Aging increases malignant peritoneal mesothelioma metastasis
Authors: Miller Mykayla 
Published: June 2023

Abstract
Mesothelioma is a rare cancer with approximately 3,000 new cases each year. There are three types of mesotheliomas including pleural (75%), pericardial (&gt;1%) and peritoneal (20%). Mesothelioma occurs in the mesothelial cells, which form a protective barrier to multiple organs. Malignant peritoneal mesothelioma (MPM) is initiated in the peritoneum, a serous membrane that lines the inner walls of the abdominal cavity and the outside of the visceral organs and is a very receptive environment for malignancy and metastasis. MPM metastasizes to the abdominal cavity, affecting the omentum, liver, stomach, intestines, and kidneys. MPM is extremely difficult to diagnose due to its vague symptoms, such as abdominal distension, abdominal pain, weight loss, and nausea. Due to difficulty in diagnosis, most patients are diagnosed at an advanced disease (stage III or IV) with a very poor prognosis with a 9% 5-year survival rate. Asbestos exposure is a major risk factor for MPM with symptoms taking 20-50 years post- exposure to appear, making MPM prominent in aged adults. Mesothelin (MSLN), a 40 kDa protein, is normally expressed on the surface of mesothelial cells and manifests at abnormally high levels in several carcinomas including malignant peritoneal mesothelioma. The exact role of mesothelin is not yet fully understood as mesothelin knockout mice do not display an abnormal phenotype. However, there is some evidence to suggest that mesothelin is involved in tumor cell adhesion by binding to the tumor antigen MUC16. Mesothelin wild-type (WT) and knockout (KO) mice were used to investigate the role of host mesothelin expression on MPM metastasis. A MPM cell line was tagged with nuclear red fluorescence protein (RFP) and injected into the abdomen of female C57Bl/6, young (3-6 months) and aged (18-23 months), MSLN WT or KO mice. Disease progression was evaluated post injection of tumor cells by fluorescent in vivo imaging prior to end point dissection. The abdominal cavity was imaged in situ and tumor burden was evaluated using Image J. Overall, aged mice had increased abdominal tumor burden regardless of host MSLN expression. Aged MSLN KO mice displayed an increase in abdominal tumor burden compared to aged MSLN WT mice, however this difference was not significant. Interestingly, the immune profile of the abdominal cavity of tumor naive mice displays a decrease in natural killer (NK) cells and peritoneal macrophages in aged mice suggesting a role in regulating metastatic peritoneal mesothelioma and could possibly be targets for new immunotherapies. This study demonstrates host age increases tumor growth and metastatic success in peritoneal mesothelioma.
Citation Format: Mykayla Miller. Aging increases malignant peritoneal mesothelioma metastasis [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 1329.
Abstract 1332: Extracted mRNA from frozen buffy coat samples shows promise for use in downstream sequencing analyses
Authors: Ylitalo Erik Bovinder , Vidman Linda , Harlid Sophia , Van Guelpen Bethany 
Published: June 2023

Abstract
Frozen blood samples are routinely collected and stored in medical biobanks across the world, often for periods of several decades, and later used for medical research such as biomarker studies. Some common biomarker targets have included DNA alterations, protein or antibody levels or metabolomics. However, despite the potential importance of gene-expression alterations in circulating immune cells, transcriptional studies on blood samples from biobanks have been limited due to preanalytical technical difficulties of extracting high-quality RNA. In the absence of an RNA preservative, RNA degrades rapidly during the thawing process. Our aim was, therefore, to investigate the possibility of using biobanked blood samples for transcriptomics analyses. First, we used a CryoXtract CXT 350 to establish a protocol capable of isolating high-quality RNA from frozen core aliquots of buffy coat without thawing the entire sample tube. Then, we performed RNA sequencing on RNA extracted from 20 pre-diagnostic buffy coat samples from colorectal cancer patients and matched controls included in the population-based, prospective Northern Sweden Health and Disease Study (NSHDS). For all samples, two different library preparation methods were used (Illumina TruSeq Stranded mRNA poly-A selection and Illumina Stranded Total RNA with Ribo-Zero Globin). We obtained RNA yields of more than 1 µg from a majority of the NSHDS samples (mean=2.57 µg), and more than 92% of samples had RIN values of 6 or higher, indicating suitability for downstream analyses. Preliminary random forest analyses showed expected discriminatory ability between men and women based on data generated from each of the two library preparation methods. In conclusion, our newly established RNA extraction method enables extraction of RNA from frozen, biobanked buffy coat samples, collected in standard tubes, that is of sufficient quantity and quality for use in downstream whole-genome transcriptomic analyses, such as RNA sequencing.
Citation Format: Erik Bovinder Ylitalo, Linda Vidman, Sophia Harlid, Bethany Van Guelpen. Extracted mRNA from frozen buffy coat samples shows promise for use in downstream sequencing analyses [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 1332.
Abstract 1407: Refining endometrial carcinoma of no-specific molecular subtype by sources of estrogen signaling
Authors: Lam Clarissa , Aghajanian Carol , Abu-Rustum Nadeem , Weigelt Britta , Ellenson Lora , Boroujeni Amir Momeni 
Published: June 2023

Abstract
Introduction: Endometrial carcinomas (ECs) of no-specific molecular profile (NSMP-EC) are a large and heterogenous group of tumors. These cancers, in particular endometrioid carcinomas, are thought to be dependent on or benefit from estrogen receptor (ER) signaling. In this study, we sought to determine the sources of ER signaling in patients with NSMP-EC.
Methods: We compiled a retrospective database of EC patients who received their primary treatment at our institution from 2014 to 2022, and who had ECs of NSMP based on a surrogate of The Cancer Genome Atlas (TCGA) prognostic EC molecular subtype. We used ovarian volume (binarized using a cutoff of 40 cm3), menopausal status, body mass index (BMI&gt;25), and ESR1 hotspot mutations as surrogate markers for ER signaling.
Results: A total of 171 patients with NSMP-EC were included in this study. As expected, menopausal status was correlated with ovarian volume (right ovarian volume median 12.3 cm3 vs 32.8 cm3, p=0.001; left ovarian volume median 10.6 cm3 vs 37.7 cm3, p&lt;0.001). Of these 171 patients, 135 (79%) had an identifiable source of ER signaling. Tumors with ER signaling sources tended to be endometrioid carcinomas (125/135, 93%) whereas a lower proportion of ECs without ER signaling were of endometrioid histology (24/36, 67%; p=0.001). ESR1 hotspot mutations almost exclusively occurred in post-menopausal (11/12 mutated cases) and older patients (median age 69 vs 61 years, p=0.012). PTEN mutations tended to be more frequent in ECs with ER signaling source (70% vs. 50%, P=0.036); in contrast, KRAS hotspot mutations were more common in cases without an identifiable ER source (42% vs. 24%, p=0.067). Additionally, the presence of PTEN mutations was associated with a higher BMI (median 31.1 vs 28.3, p=0.012), whereas FBXW7 mutations were associated with a lower BMI (median 24 vs 30.6, p=0.047). Log-rank survival analysis showed that patients whose ECs lacked an identifiable ER signaling source had a markedly worse survival outcome (p=0.0024).
Discussion: We demonstrate that the majority of NSMP-ECs have an identifiable ER signaling source. The minority of NSMP-ECs lacking an ER signaling source may not only represent a hormonally independent tumorigenesis but are also markedly distinct at the molecular, pathologic, and clinical levels. ER protein immunohistochemistry may help in further defining these groups.
Citation Format: Clarissa Lam, Carol Aghajanian, Nadeem Abu-Rustum, Britta Weigelt, Lora Ellenson, Amir Momeni Boroujeni. Refining endometrial carcinoma of no-specific molecular subtype by sources of estrogen signaling [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 1407.
Abstract 1535: A novel ELISA Kit:highly accuracy and sensitivity for GDF-15 detection
Authors: Liang Meng , He Feng , Zhang Meng , Ye Yinsong , Chen Shukun , Ning Jinying , Hao Feng 
Published: June 2023

Abstract
Growth/differentiation factor 15 (GDF-15) is a promising drug target and biomarker for cancer early screening or immunotherapy. Under normal conditions, GDF-15 is expressed in low concentrations in most organs. Increased protein levels are associated with disease states such as tissue hypoxia, inflammation, acute injury and oxidative stress. The development of GDF-15 detection kit can help pharmaceutical companies in the early stage of drug development. It can also facilitate the early screening of related diseases. Hence, we developed a novel GDF-15 detected ELISA kit based on double-antibody sandwich ELISA. Our kit has ultra-high sensitivity and specificity and the concentration of GDF-15 can be detected accurately in complex biological samples such as serum, plasma or urine. First of all, mice were immunized by GDF-15. After detecting the antibody titers in sera of the immunized mice, hybridoma technologies were used to produce GDF-15 monoclonal antibodies. 57 antibodies were analyzed by epitope competition, ELISA binding and KD binding detection. The specificity of pairwise candidates was screened to obtain optimal coating and detecting antibody pair. The detecting antibody was labeled with biotin which can be conjugated with streptavidin labeled HRP. Biotin-streptavidin labeling detection method can achieve signal amplification which offers an improved detection sensitivity. Our GDF-15 detection kit has better property in sensitivity and specificity. The detection range is from 10 pg/mL to 10000 pg/mL. LOD is 5 pg/mL and LOQ is 10 pg/mL. These parameters are better than many commercial test kits. Moreover, the concentration of GDF-15 can be detected accurately in complex clinical samples. We anticipate that this GDF-15 detection kit can be applied not only for companion diagnosis, but also for related drug development.
Citation Format: Meng Liang, Feng He, Meng Zhang, Yinsong Ye, Shukun Chen, Jinying Ning, Feng Hao. A novel ELISA Kit:highly accuracy and sensitivity for GDF-15 detection [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 1535.
Abstract 1536: Machine learning guided engineering of nivolumab for superior physicochemical properties for subcutaneous injection
Authors: Hamamatsu Norio , Kuwabara Naoyuki , Suzuki Emi , Yamazaki Ryo , Oikawa Misaki , Tawara Tomonori , Ito Tomoyuki , Nakazawa Hikaru , Kataoka Shiro , Umetsu Mitsuo 
Published: June 2023

Abstract
Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody that is used as a type of cancer immunotherapeutic agent, called a checkpoint inhibitor. Nivolumab is administered by intravenous infusion. Given the recent studies and potential demand for maintenance immunotherapy, the next generation of Nivolumab for subcutaneous injection would be beneficial for patients’ quality of life. We studied whether we could create a Nivolumab variant that has superior physicochemical properties required for a subcutaneous formulation. A machine-learning guided protein engineering technique was used to improve structural stability at little cost of affinity. As a result, a variant showed an increased melting temperature by 10 ºC with a comparable affinity to Nivolumab. Consistent with the result, the variant is resistant to aggregation under heat stress. Nivolumab is seriously aggregated after treatment at 60 ºC, while the variant does not show any aggregation at all. We also present a result of risk assessment of aggregation at high concentrations.
Citation Format: Norio Hamamatsu, Naoyuki Kuwabara, Emi Suzuki, Ryo Yamazaki, Misaki Oikawa, Tomonori Tawara, Tomoyuki Ito, Hikaru Nakazawa, Shiro Kataoka, Mitsuo Umetsu. Machine learning guided engineering of nivolumab for superior physicochemical properties for subcutaneous injection [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 1536.
Abstract 1668: Targeting drug-induced tolerant & resistant cell populations by novel ferroptosis inducer
Authors: Dubash Taronish , Munteanu Maria Cristina , Farah Shrouq , Nunez Cristian , Jadin Laurence , Radetich Branko , Schmidt Darby , Gurvich Nadia 
Published: June 2023

Abstract
A subset of tumor cells escapes apoptotic and necroptotic death when subjected to chemo- or targeted therapy thereby entering a transient reversible less-proliferative “tolerant state.” Upon continuous drug treatment, these tumor cells become drug resistant, leading to metastases and cancer relapse. A long-standing goal in oncology has been to develop therapeutics to effectively target both cell states. Growing published evidence suggests that accumulation of reactive oxygen species and lipid remodeling make tolerant and resistant tumor cells more vulnerable to ferroptotic mode of cell death. To this end, we here characterize the activity of a proprietary inhibitor of GPX4, an enzyme that safeguards against ferroptosis, across a panel of tolerant and resistant cell line models. Drug tolerant and resistant cancer cell lines spanning three indications were generated by applying continuous treatments with relevant standard-of-cares (SOC) in vitro for short or long durations, respectively. Age-matched control cell lines were derived in parallel by treatment of parental cells with DMSO. Cells were subjected to high dose of SOC for nine days to generate tolerant lines, or to increased therapeutic doses of SOC over three months to generate resistant lines, after which resistance to SOCs was confirmed. In accordance with our hypothesis, we found that drug tolerant lines demonstrated enhanced sensitivity to GPX4 inhibition compared to age-matched control lines. Furthermore, we noted that resistant tumor cell lines retained exquisite sensitivity to GPX4 inhibition across all indications while demonstrating up to 1000-fold resistance to SOCs. In summary, we found that cell line models which evade cell death upon treatment with chemo- or targeted therapies continued to present vulnerability to ferroptosis induction across both cell states. Given the heterogeneity in responses to drug-induced cell-states, understanding the mechanisms of differential drug sensitivity to GPX4 inhibition may help in formulating successful strategies for targeting this relevant cell population in the clinic, thereby limiting cancer progression and/or improving curative potential.
Citation Format: Taronish Dubash, Maria Cristina Munteanu, Shrouq Farah, Cristian Nunez, Laurence Jadin, Branko Radetich, Darby Schmidt, Nadia Gurvich. Targeting drug-induced tolerant & resistant cell populations by novel ferroptosis inducer [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 1668.
Abstract 1692: mTOR inhibition attenuates chemosensitivity through induction of a persister state
Authors: Liu Yuanhui , Azizian Nancy , Sullivan Delaney , Li Yulin 
Published: June 2023

Abstract
Effective cancer therapeutics often kill a large fraction of tumor cells, while sparing a small surviving population, which can resurface as future tumor recurrence. Mechanisms of resistance in these residual tumors may involve rare preexisting clones with mutations, as well as de novo development of resistance through various genetic and/or non-genetic processes. In the context of acute stress resulting from cancer therapeutics, the initial adaptation is essential for tumor cell survival and allows for subsequent development of resistance through additional genetic and non-genetic mechanisms. As an integrator of environmental signals and cellular response, the mTOR pathway is a critical driver of cellular adaptation to environmental changes. In particular, mTOR regulates embryonic diapause, a reversible dormancy state in mammalian development in response to unfavorable environments. Analogous to its role in regulating embryonic diapause, mTOR inhibition may induce a diapause-like state in cancer cells, leading to drug tolerance and persistence of residual tumors following therapy. In line with this notion, recent studies have reported markedly reduced mTOR activity in residual tumors. However, the causal relationship between mTOR inhibition and chemosensitivity has not been investigated. Through a genome-wide CRISPR knockout library screen in pancreatic cancer cells treated with chemotherapeutic agents, we have identified the mTOR pathway as a prominent determinant of chemosensitivity. Pharmacological suppression of mTOR activity in cancer cells from diverse tissue origins leads to the persistence of a reversibly resistant population, which is otherwise eliminated by chemotherapeutic agents. Conversely, activation of the mTOR pathway increases chemosensitivity and predicts better survival among various human cancers. Survival of the persisters is dependent on the regulation of autophagy, G2/M checkpoint, and cell death pathways, as revealed by a small-molecule chemical library screen. Thus, mTOR plays a causal yet paradoxical role in regulating chemotherapeutic response; inhibition of the mTOR pathway, while suppressing tumor expansion, facilitates the development of a reversible drug-tolerant persister state.
Citation Format: Yuanhui Liu, Nancy Azizian, Delaney Sullivan, Yulin Li. mTOR inhibition attenuates chemosensitivity through induction of a persister state [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 1692.