bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel banana lectin CAR-T cells to target pancreatic tumors and tumor-associated stroma
Authors: McKenna Mary K , Ozcan Ada , Brenner Daniel , Watanabe Norihiro , Legendre Maureen , Thomas Dafydd G , Ashwood Christopher , Cummings Richard D , Bonifant Challice , Markovitz David M , Brenner Malcolm K 
Published: January 2023

BackgroundCell therapies for solid tumors are thwarted by the hostile tumor microenvironment (TME) and by heterogeneous expression of tumor target antigens. We address both limitations with a novel class of chimeric antigen receptors based on plant lectins, which recognize the aberrant sugar residues that are a ‘hallmark’ of both malignant and associated stromal cells. We have expressed in T cells a modified lectin from banana, H84T BanLec, attached to a chimeric antigen receptor (H84T-CAR) that recognizes high-mannose (asparagine residue with five to nine mannoses). Here, we tested the efficacy of our novel H84T CAR in models of pancreatic ductal adenocarcinoma (PDAC), intractable tumors with aberrant glycosylation and characterized by desmoplastic stroma largely contributed by pancreatic stellate cells (PSCs).MethodsWe transduced human T cells with a second-generation retroviral construct expressing the H84T BanLec chimeric receptor, measured T-cell expansion, characterized T-cell phenotype, and tested their efficacy against PDAC tumor cells lines by flow cytometry quantification. In three-dimensional (3D) spheroid models, we measured H84T CAR T-cell disruption of PSC architecture, and T-cell infiltration by live imaging. We tested the activity of H84T CAR T cells against tumor xenografts derived from three PDAC cell lines. Antitumor activity was quantified by caliper measurement and bioluminescence signal and used anti-human vimentin to measure residual PSCs.ResultsH84T BanLec CAR was successfully transduced and expressed by T cells which had robust expansion and retained central memory phenotype in both CD4 and CD8 compartments. H84T CAR T cells targeted and eliminated PDAC tumor cell lines. They also disrupted PSC architecture in 3D models in vitro and reduced total tumor and stroma cells in mixed co-cultures. H84T CAR T cells exhibited improved T-cell infiltration in multicellular spheroids and had potent antitumor effects in the xenograft models. We observed no adverse effects against normal tissues.ConclusionsT cells expressing H84T CAR target malignant cells and their stroma in PDAC tumor models. The incorporation of glycan-targeting lectins within CARs thus extends their activity to include both malignant cells and their supporting stromal cells, disrupting the TME that otherwise diminishes the activity of cellular therapies against solid tumors.
Statin drugs enhance responses to immune checkpoint blockade in head and neck cancer models
Authors: Kansal Vikash , Burnham Andre J , Kinney Brendan L C , Saba Nabil F , Paulos Chrystal , Lesinski Gregory B , Buchwald Zachary S , Schmitt Nicole C 
Published: January 2023

BackgroundAnti-PD-1 immune checkpoint blockade is approved for first-line treatment of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but few patients respond. Statin drugs (HMG-CoA reductase inhibitors) are associated with superior survival in several cancer types, including HNSCC. Emerging data suggest that manipulation of cholesterol may enhance some aspects of antitumor immunity.MethodsWe used syngeneic murine models (mouse oral cancer, MOC1 and TC-1) to investigate our hypothesis that a subset of statin drugs would enhance antitumor immunity and delay tumor growth.ResultsUsing an ex vivo coculture assay of murine cancer cells and tumor infiltrating lymphocytes, we discovered that all seven statin drugs inhibited tumor cell proliferation. Simvastatin and lovastatin also enhanced T-cell killing of tumor cells. In mice, daily oral simvastatin or lovastatin enhanced tumor control and extended survival when combined with PD-1 blockade, with rejection of MOC1 tumors in 30% of mice treated with lovastatin plus anti-PD-1. Results from flow cytometry of tumors and tumor-draining lymph nodes suggested T cell activation and shifts from M2 to M1 macrophage predominance as potential mechanisms of combination therapy.ConclusionsThese results suggest that statins deserve further study as well-tolerated, inexpensive drugs that may enhance responses to PD-1 checkpoint blockade and other immunotherapies for HNSCC.
Novel combination strategy of high intensity focused ultrasound (HIFU) and checkpoint blockade boosted by bioinspired and oxygen-supplied nanoprobe for multimodal imaging-guided cancer therapy
Authors: Tang Rui , He Hongye , Lin Xiaohong , Wu Nianhong , Wan Li , Chen Qiaoqi , Hu Yaqin , Cheng Chen , Cao Yuting , Guo Xun , Zhou Ying , Xiong Xialin , Zheng Min , Wang Qi , Li Faqi , Zhou Yang , Li Pan 
Published: January 2023

BackgroundHigh-intensity focused ultrasound (HIFU) has shown considerable promise in treating solid tumors, but its ultrasonic energy is easily attenuated, resulting in insufficient energy accumulation in the target area. Moreover, HIFU ablation alone may inevitably lead to the presence of residual tumors, which may cause tumor recurrence and metastasis. Here, we describe a synergistic regimen combining HIFU facilitation with immunomodulation based on a novel oxygen-carrying biomimetic perfluorocarbon nanoparticle (M@P-SOP) to stimulate immunogenic cell death in tumor cells while alleviating immune suppression tumor microenvironment.MethodsM@P-SOP was prepared by double emulsion and film extrusion method. The anticancer and antimetastatic effects of M@P-SOP were evaluated on a preclinical transplanted 4T1 tumor model by combining HIFU and immunotherapy. Flow cytometry and immunofluorescence were used to clarify the potential mechanism of HIFU+M@P-SOP and their role in anti-programmed death ligand-1 (PD-L1) therapy.ResultsGuided by photoacoustic/MR/ultrasound (US) multimodal imaging, M@P-SOP was abundantly enriched in tumor, which greatly enhanced HIFU’s killing of tumor tissue in situ, induced stronger tumor immunogenic cell death, stimulated dendritic cell maturation and activated CD8+T cells. At the same time, M@P-SOP released oxygen to alleviate the tumor hypoxic environment, repolarizing the protumor M2-type macrophages into antitumor M1-type. With concurrent anti-PD-L1 treatment, the antitumor immune response was further amplified to the whole body, and the growth of mimic distant tumor was effectively suppressed.ConclusionsOur findings offer a highly promising HIFU synergist for effectively ameliorating acoustic and hypoxia environment, eventually inhibiting tumor growth and metastasis by stimulating host’s antitumor immunity under HIFU ablation, especially in synergizing with PD-L1 antibody immunotherapy.
Deep learning-based personalised outcome prediction after acute ischaemic stroke
Authors: Kim Doo-Young , Choi Kang-Ho , Kim Ja-Hae , Hong Jina , Choi Seong-Min , Park Man-Seok , Cho Ki-Hyun 
Published: January 2023

BackgroundWhether deep learning models using clinical data and brain imaging can predict the long-term risk of major adverse cerebro/cardiovascular events (MACE) after acute ischaemic stroke (AIS) at the individual level has not yet been studied.MethodsA total of 8590 patients with AIS admitted within 5 days of symptom onset were enrolled. The primary outcome was the occurrence of MACEs (a composite of stroke, acute myocardial infarction or death) over 12 months. The performance of deep learning models (DeepSurv and Deep-Survival-Machines (DeepSM)) and traditional survival models (Cox proportional hazards (CoxPH) and random survival forest (RSF)) were compared using the time-dependent concordance index (Ctdindex).ResultsGiven the top 1 to all 60 clinical factors according to feature importance, CoxPH and RSF yieldedCtdindex of 0.7236–0.8222 and 0.7279–0.8335, respectively. Adding image features improved the performance of deep learning models and traditional models assisted by deep learning models. DeepSurv and DeepSM yielded the bestCtdindex of 0.8496 and 0.8531 when images were added to all 39 relevant clinical factors, respectively. In feature importance, brain image was consistently ranked highly. Deep learning models automatically extracted the image features directly from personalised brain images and predicted the risk and date of future MACEs at the individual level.ConclusionsDeep learning models using clinical data and brain images could improve the prediction of MACEs and provide personalised outcome prediction for patients with AIS. Deep learning models will allow us to develop more accurate and tailored prognostic prediction systems that outperform traditional models.
Impact of psoriatic arthritis and comorbidities on ustekinumab outcomes in psoriasis: a retrospective, observational BADBIR cohort study
Authors: Tillett William , Ogdie Alexis , Passey Alun , Gorecki Patricia 
Published: January 2023

ObjectivesPsoriasis and psoriatic arthritis (PsA) are independently associated with comorbidities, including obesity and metabolic syndrome, which may impact treatment outcomes. This study aimed to assess baseline differences between patients with plaque psoriasis alone and those with concomitant PsA, and to investigate the impact of these characteristics on ustekinumab (UST) persistence and outcomes.Methods9057 patients receiving UST or conventional systemic disease-modifying antirheumatic drugs were selected from the British Association of Dermatologists Biologic and Immunomodulators Register. The psoriasis and PsA cohorts were compared at baseline. Time to discontinuation during 10-year follow-up was assessed using multivariable Cox regression and Kaplan–Meier analyses, stratifying for interacting covariates and PsA status. Generalised linear mixed models assessed the impact of baseline characteristics on Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index over time.ResultsGreater comorbidity burden, including hypertension, diabetes, obesity and depression, and greater inability to work were observed in the PsA cohort than in the psoriasis cohort. PsA (HR 1.98), female sex (HR for male sex 0.72) and depression (HR 1.21) were associated with shorter UST persistence. PsA showed a differential association with UST persistence by PASI strata and prior biologic exposure. Quality of life was negatively impacted by depression and PsA.ConclusionsThe negative impact of comorbidities on treatment persistence identified in this study emphasises the need for patient-centric, multidisciplinary care in screening for and managing comorbidities in psoriasis and PsA treatment. Psychological support and lifestyle management of modifiable risk factors, including obesity, should be considered.
The Use of Exploratory Software Testing in SCRUM
Authors: Neri Giulia R. 
Published: January 2023

Exploratory testing is a very common, yet under researched, software testing technique. Research has shown how this technique can provide a better insight about the system under test than other techniques, that it can find defects more efficiently than other testing approaches and even aid the design of other techniques.
This research aims at increasing the understanding of exploratory testing and the way it is used within industries utilizing SCRUM. Another aim is to identify and understand the factors that enable the tester to use this technique successfully. The decision to set the study in SCRUM comes from the fact that this Agile management framework is the most popular in industry and from the suggestion to focus on the relationship between Agile and exploratory testing. Also, the choice of a specific context adds significance to the findings.
This research will be conducted in a Sheffield based company, which produces data analytics software. The methodology will consist of three phases. During Phase 1 (Identification), SCRUM practitioners will be interviewed about the use of exploratory testing in SCRUM and the success factors of this technique. The aim of Phase 2 (Confirmation) will be to confirm the findings from Phase 1.
This will be accomplished with focus groups and widely-distributed online survey. Finally, during Phase 3 (Verification), practitioners will take part to experiments to verify that the success factors identified during the first two phases enable efficient and effective exploratory testing.
The purpose of this research is to enrich the academic field of software verification and validation, but also to provide industries utilising SCRUM with useful guidance.
Dual mTORC1/2 Inhibition Synergistically Enhances AML Cell Death in Combination with the BCL2 Antagonist Venetoclax
Authors: Satta Toshihisa , Li Lin , Chalasani Sri Lakshmi , Hu Xiaoyan , Nkwocha Jewel , Sharma Kanika , Kmieciak Maciej , Rahmani Mohamed , Zhou Liang , Grant Steven 
Published: January 2023

AbstractPurpose:Acute myelogenous leukemia (AML) is an aggressive disease with a poor outcome. We investigated mechanisms by which the anti-AML activity of ABT-199 (venetoclax) could be potentiated by dual mTORC1/TORC2 inhibition.Experimental Design:Venetoclax/INK128 synergism was assessed in various AML cell lines and primary patient AML samples in vitro. AML cells overexpressing MCL-1, constitutively active AKT, BAK, and/or BAX knockout, and acquired venetoclax resistance were investigated to define mechanisms underlying interactions. The antileukemic efficacy of this regimen was also examined in xenograft and patient-derived xenograft (PDX) models.Results:Combination treatment with venetoclax and INK128 (but not the mTORC1 inhibitor rapamycin) dramatically enhanced cell death in AML cell lines. Synergism was associated with p-AKT and p-4EBP1 downregulation and dependent upon MCL-1 downregulation and BAK/BAX upregulation as MCL-1 overexpression and BAX/BAK knockout abrogated cell death. Constitutive AKT activation opposed synergism between venetoclax and PI3K or AKT inhibitors, but not INK128. Combination treatment also synergistically induced cell death in venetoclax-resistant AML cells. Similar events occurred in primary patient-derived leukemia samples but not normal CD34+ cells. Finally, venetoclax and INK128 co-treatment displayed increased antileukemia effects in in vivo xenograft and PDX models.Conclusions:The venetoclax/INK128 regimen exerts significant antileukemic activity in various preclinical models through mechanisms involving MCL-1 downregulation and BAK/BAX activation, and offers potential advantages over PI3K or AKT inhibitors in cells with constitutive AKT activation. This regimen is active against primary and venetoclax-resistant AML cells, and in in vivo AML models. Further investigation of this strategy appears warranted.
Abstract A018: Abiraterone vs. enzalutamide: Does age impact one treatment over another
Authors: Nikita Nikita , Shaver Amy , Gandhi Krupa , Keith Scott W. , Sharma Swapnil , Lu-Yao Grace 
Published: January 2023

Abstract
Background: Abiraterone and Enzalutamide are two of the most commonly used treatments for prostate cancer (PCa). Currently, both these medications are approved for similar clinical indications even though they have different toxicity profiles. This study aims to identify if patients and providers prefer one medication to another and if the choice depends on age. Methods: We used SEER-Medicare data to identify primary PCa patients diagnosed between 1999 and 2017. We excluded those diagnosed at death. Abiraterone and enzalutamide use was identified using part D files. Patients had 6 months continuous part D coverage prior to treatment. Age was parameterized categorically: 65-74 years, 75-84 years, and over 85 years. Descriptive statistics were generated and evaluated by Chi-square tests for all categorical variables. Multivariable logistic regression was used to investigate disparities between the treatments adjusting for demographic characteristics. Results: We identified 8,398 patients with PCa over 65 years of age; 4,180 used abiraterone and 4,218 used enzalutamide. The demographic characteristics for both groups were similar (p = 0.1557). Most patients were 65-74 years old (62.6% in the abiraterone group and 62.4% in the enzalutamide group), followed by approximately 30% of each group in the 75-84 age range. Finally, the enzalutamide group had 8.2% 85 years and older, while the abiraterone group had 7.1%. The appeared to be no preference in odds of use of either medication by age group. When comparing the very old (85+) to the 65-74 year olds (OR=0.906; 95% CI 0.745, 1.101; p=0.3727). Nor was there a statistical significance when comparing odds of use between 75-84-year-olds to those who were 65-74 (OR=0.978; 95%CI 0.873, 1.095; p=0.6927). Conclusion: Our study found that abiraterone and enzalutamide use among patients does not differ substantially by age groups. Further studies are warranted to understand these associations better.
Citation Format: Nikita Nikita, Amy Shaver, Krupa Gandhi, Scott W. Keith, Swapnil Sharma, Grace Lu-Yao. Abiraterone vs. enzalutamide: Does age impact one treatment over another [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A018.
Abstract A021: Older adult-specific microbes correlate with treatment response and markers of T-cell senescence in NSCLC
Authors: Spakowicz Daniel , Hoyd Rebecca , Wheeler Caroline E. , Williams Nyelia , Bibi Amna , Husain Marium , Rajamouli Srichandhana , Suman Shankar , Amann Joseph , Grogan Madison , Vibhakar Pooja , Owen Dwight H. , Carbone David P. , Rosko Ashley , Burd Christin E. , Presley Carolyn J. 
Published: January 2023

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Short Talks from Proffered Abstracts section (PR004) of the Conference Proceedings.
Citation Format: Daniel Spakowicz, Rebecca Hoyd, Caroline E. Wheeler, Nyelia Williams, Amna Bibi, Marium Husain, Srichandhana Rajamouli, Shankar Suman, Joseph Amann, Madison Grogan, Pooja Vibhakar, Dwight H. Owen, David P. Carbone, Ashley Rosko, Christin E. Burd, Carolyn J. Presley. Older adult-specific microbes correlate with treatment response and markers of T-cell senescence in NSCLC [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A021.
Abstract IA011: Mutations in normal cell
Authors: Stratton Mike 
Published: January 2023

Abstract
Mutations in DNA/RNA cause the phenotypic variation upon which natural selection acts during evolution. Mutations arise and are transmitted between generations of organisms and between generations of cells in the somatic tissues of multicellular organisms. However, our knowledge of the biological processes that generate mutations and the rates at which they occur in different cell types has been rudimentary until recently. Cancer is a recognized outcome of somatic mutations. However, we have limited understanding of the wider consequences of somatic mutations. I will review our current understanding of the landscape of somatic mutations in normal cells, its causes and its consequences.
Citation Format: Mike Stratton. Mutations in normal cell [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA011.
Abstract IA013: Age-related changes in pancreatic fibroblasts drive pancreatic cancer growth and progression
Authors: Zabransky Daniel , Jaffee Elizabeth , Weeraratna Ashani 
Published: January 2023

Abstract
Aging is an independent risk factor for the development of pancreatic ductal adenocarcinoma (PDAC). However, the ways in which aging alters cell populations that will ultimately comprise the PDAC tumor microenvironment (TME) are incompletely understood. PDAC tumors are highly desmoplastic, and fibroblasts alter the behavior of pancreatic cancer cells and impact treatment responses. Here, we show that normal pancreatic fibroblasts acquire tumor-promoting properties during aging using both in vitro and in vivo models. To determine if PDAC tumors may be influenced by an aged microenvironment, we performed orthotopic KPC cell injections into the pancreata of aged (&gt;52-week-old) and young (6-8-week-old) syngeneic C57Bl/6J mice. Aged mice have significantly larger tumors, increased incidence of liver metastases, and decreased survival compared to young mice. We next queried whether aged pancreatic fibroblasts contribute to this increase in tumor growth. We generated a panel of aged (donors &gt;55 years old) and young (donors &lt;35 years old) normal human pancreatic fibroblasts to determine the effects of healthy aging fibroblasts on PDAC cell behavior. Conditioned media from aged human pancreatic fibroblasts significantly increases the proliferation of PDAC cells, suggesting that secreted factors produced by aged fibroblasts enhance cancer cell growth. Next, we evaluated changes in the invasiveness of PDAC cells in a 3D co-culture system with either aged or young pancreatic fibroblasts. PDAC spheroids containing cancer cells and aged fibroblasts exhibit a significant increase in invasiveness compared to those containing young fibroblasts. Aged (&gt;52-week-old) compared to young (6-8-week-old) mouse pancreatic fibroblasts also increase the proliferation and invasiveness of KPC cells in vitro, providing evidence that aged fibroblasts may contribute to the phenotypes observed in vivo experiments using aged mouse models. In conclusion, we show that aged, non-cancer-associated pancreatic fibroblasts have the potential to promote growth, migration, and invasiveness in multiple models of pancreatic ductal adenocarcinoma. We hypothesize that factors secreted by pancreatic fibroblast change during aging and that this aged secretome may serve to establish a tumor-promoting niche for pancreatic cancer cells.
Citation Format: Daniel Zabransky, Elizabeth Jaffee, Ashani Weeraratna. Age-related changes in pancreatic fibroblasts drive pancreatic cancer growth and progression [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA013.