bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fused Granulated Fabrication (FGF) Processing Study for Novel sCF/LMPAEK Recycled Material to Manufacture Aeronautic Structural Parts
Authors: Martín-Pérez Celia , Rodriguez-Del Rosario Daniel , Rodríguez-Senín Elena , González-Castro Noelia 
Published: January 2023

Abstract
ECO-CLIP has developed a novel recycled 40wt% short CF/LMPAEK material from factory scrap that has been used to manufacture aircraft structural parts using injection molding (IM), the conventional manufacturing process, and fussed granulated fabrication (FGF) as an alternative one.
In this sense, a technical study of the material processability has been made for FGF. The most important results are presented in this work, such as fiber breakage, carbon fiber percentage after and before processing, thermal behavior and thermal induce history, and mechanical properties such as compression, tensile and flexural behavior Three different nozzle diameters (0.8, 1.2, and 1.5mm) were used to ensure processability, mechanical requirements, and physical performance. Carrying out a direct comparison with the results achieved by IM.
Other PAEKs have been processed by FGF or traditional fused filament fabrication (FFF) for comparative purposes.
Development of Adaptive Toolpaths for Repair and Cladding of Complex 3D Components by Laser Metal Deposition
Authors: Ortiz Igor , Álvarez Piera , Montealegre Maria Angeles , Cordovilla Francisco , Ocaña José Luis 
Published: January 2023

Abstract
The paper envisages the development of specific toolpaths for additive repair and cladding of full 3D geometry components by the Laser Metal Deposition Additive Manufacturing technique. Due to the essential difference between substractive and additive manufacturing approaches, the use of traditional substractive CAD-CAM programs is hardly suitable for a proper design and manufacturing of 3D additive manufactured AM’d components. The main key points for the development of CAD-CAM tools specifically applicable to Additive Manufacturing - AM processes are the need for an intrinsic process stability in terms of coating and layer growth, the need for a well-tailored additive track overlapping over the whole selected surface area and the need for integration of specific features relative to the laser, addition material and surface properties monitoring and control. The expected result of the full AM process based on the appropriate design tools is an efficient capability to meet not only the full 3D geometry according to the specified tolerances, but, very importantly, the microstructure specifications for the deposited material, avoiding the existence of critical defaults invalidating the fabrication or repair of the component. Moreover, the developed AZALA software must comply with the geometric specifications usual for manufacturing workstations, detecting preventively possible part-tool collisions with part and assuring an overall efficient manufacturing chain.
Tasquinimod suppresses tumor cell growth and bone resorption by targeting immunosuppressive myeloid cells and inhibiting c-MYC expression in multiple myeloma
Authors: Fan Rong , Satilmis Hatice , Vandewalle Niels , Verheye Emma , Vlummens Philip , Maes Anke , Muylaert Catharina , De Bruyne Elke , Menu Eline , Evans Holly , Chantry Andrew , De Beule Nathan , Hose Dirk , Törngren Marie , Eriksson Helena , Vanderkerken Karin , Maes Ken , Breckpot Karine , De Veirman Kim 
Published: January 2023

BackgroundImmunotherapy emerged as a promising treatment option for multiple myeloma (MM) patients. However, therapeutic efficacy can be hampered by the presence of an immunosuppressive bone marrow microenvironment including myeloid cells. S100A9 was previously identified as a key regulator of myeloid cell accumulation and suppressive activity. Tasquinimod, a small molecule inhibitor of S100A9, is currently in a phase Ib/IIa clinical trial in MM patients (NCT04405167). We aimed to gain more insights into its mechanisms of action both on the myeloma cells and the immune microenvironment.MethodsWe analyzed the effects of tasquinimod on MM cell viability, cell proliferation and downstream signaling pathways in vitro using RNA sequencing, real-time PCR, western blot analysis and multiparameter flow cytometry. Myeloid cells and T cells were cocultured at different ratios to assess tasquinimod-mediated immunomodulatory effects. The in vivo impact on immune cells (myeloid cell subsets, macrophages, dendritic cells), tumor load, survival and bone disease were elucidated using immunocompetent 5TMM models.ResultsTasquinimod treatment significantly decreased myeloma cell proliferation and colony formation in vitro, associated with an inhibition of c-MYC and increased p27 expression. Tasquinimod-mediated targeting of the myeloid cell population resulted in increased T cell proliferation and functionality in vitro. Notably, short-term tasquinimod therapy of 5TMM mice significantly increased the total CD11b+cells and shifted this population toward a more immunostimulatory state, which resulted in less myeloid-mediated immunosuppression and increased T cell activation ex vivo. Tasquinimod significantly reduced the tumor load and increased the trabecular bone volume, which resulted in prolonged overall survival of MM-bearing mice in vivo.ConclusionOur study provides novel insights in the dual therapeutic effects of the immunomodulator tasquinimod and fosters its evaluation in combination therapy trials for MM patients.
INBRX-120, a CD8α-targeted detuned IL-2 that selectively expands and activates tumoricidal effector cells for safe and durable in vivo responses
Authors: Sulzmaier Florian J , Kern Nadja , Ahn Sae Jeong , Polovina Anya , Ho Jason , Hussain Abrahim , Cyprus Garrett , Macedo Chelsie , Pandit Rajay , Crago William , Rowell Emily , Timmer John C , Eckelman Brendan P 
Published: January 2023

BackgroundAs a major driver of lymphocyte proliferation and activation interleukin 2 (IL-2) is a crucial mediator for antitumor responses. Despite promising activity in a subset of patients, wider therapeutic utility of IL-2 (aldesleukin) has been hampered by severe dose-limiting toxicities, the expansion of immunosuppressive regulatory T cells and a poor pharmacokinetic (PK) profile. Recent engineering efforts, including non-α IL-2 variants, have lowered the toxicity profile, but have yet to induce meaningful antitumor activity in a wider patient population.MethodsWe engineered INBRX-120, a CD8α-targeted Cisleukin™ molecule consisting of an affinity tuned IL-2 (IL2-x) connected to two high affinity CD8α-specific single domain antibodies via an effector-silenced Fc domain. To show that this large affinity differential enables directed IL-2 cis-signaling exclusively on CD8α-expressing tumoricidal effector cell populations, INBRX-120 effects on target cell expansion, activation and antitumor activity were tested in vitro. In vivo antitumor efficacy was evaluated in syngeneic mouse models alone or in combination with programmed cell death protein-1 (PD-1) blockade. Preclinical safety, as well as pharmacodynamic (PD) and PK profiling was carried out in non-human primates.ResultsINBRX-120 effectively expanded and enhanced the cytotoxic capacity of CD8 T cells and natural killer cells towards tumor cells without affecting regulatory T cells in vitro and in vivo. In syngeneic mouse models, INBRX-120 surrogate showed safe, potent, and durable antitumor efficacy alone and in combination with PD-1 blockade. In non-human primates, INBRX-120 expanded and activated CD8α-expressing effector cells, showed a favorable PK profile, and was well tolerated up to a dose of 1 mg/kg.ConclusionsThrough its unique cis-signaling activity on CD8α-expressing effector cells, INBRX-120 overcomes the major limitations of IL-2-based therapy and effectively harnesses IL-2’s potent intrinsic antitumor activity. This novel therapeutic strategy promises safer clinical activity that could induce meaningful antitumor efficacy in a wider set of patients with various cancer indications.
Abstract A005: The aged tumor microenvironment influences tolerance to targeted therapy via NR2F1 overexpression in BRAF-mutant melanoma
Authors: Tiago Manoela , Purwin Timothy J. , Fane Mitchell E. , Chhabra Yash , Teh Jessica L. F. , Kadamb Rama , Cai Weijia , Chervoneva Inna , Rosenbaum Sheera , Chua Vivian , Hacohen Nir , Davies Michael A. , Villanieva Jessie , Weeraratna Ashani T. , Capparelli Claudia , Aguirre-Ghiso Julio A. , Aplin Andrew E. 
Published: January 2023

Abstract
Despite the clinical success of targeted inhibitors, tumor responses to these agents are transient, and drug-tolerant residual cells seed resistance. Understanding the role of tumor-intrinsic mechanisms and effects of the tumor microenvironment in mediating drug tolerance will guide and optimize targeted therapies. Given similarities between drug tolerance and cellular dormancy, we studied the role of nuclear receptor subfamily 2 group F member 1 (NR2F1) in response to targeted therapy. We used BRAF-mutant cutaneous melanoma models treated with BRAF and MEK inhibitors (BRAFi + MEKi) since patients treated with this combination typically develop resistance. The aged tumor microenvironment has been shown to increase therapy resistance, and we find that melanoma cells in aged mice express higher levels of NR2F1 than when the same cells are injected into young animals. Transcriptomic analysis of melanoma patient samples treated with BRAFi + MEKi showed increased expression of NR2F1 post-treatment. Similarly, NR2F1 was highly expressed in minimal residual disease collected on BRAFi + MEKi treatment in patient- and xenograft-derived tumors. High expression of NR2F1 promotes tumor survival and invasion in the presence of BRAFi + MEKi in vitro leading to tolerance to BRAFi + MEKi efficacy in vivo. Depletion of NR2F1 in YUMM1.7 allografts grown in aged mice improved response to the combination therapy. Altogether, our findings suggest that NR2F1 promotes drug tolerance leading to minimal residual disease in melanoma and that NR2F1-high cells may be targeted with CDK4/6 inhibitors to improve targeted therapy outcomes in melanoma patients.
Citation Format: Manoela Tiago, Timothy J. Purwin, Mitchell E. Fane, Yash Chhabra, Jessica L. F. Teh, Rama Kadamb, Weijia Cai, Inna Chervoneva, Sheera Rosenbaum, Vivian Chua, Nir Hacohen, Michael A. Davies, Jessie Villanieva, Ashani T. Weeraratna, Claudia Capparelli, Julio A. Aguirre-Ghiso, Andrew E. Aplin. The aged tumor microenvironment influences tolerance to targeted therapy via NR2F1 overexpression in BRAF-mutant melanoma [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 A005.
Abstract A023: Analysis of survival and prognostic factors for patients with non-small cell lung cancer and brain metastasis: 10-year experience in a single institution
Authors: Yang Seung Ho 
Published: January 2023

Abstract
The aims of the study were 1) to perform the review of non-small cell lung cancer (NSCLC) patients with brain metastasis in our institution, 2) to investigate the response and prognostic factor of brain metastasis after institution’s best treatment, and 3) to suggest the shift of treatment paradigms for brain metastasis. From Jan. 2007 to Oct. 2018, A total 214 NSCLC patients with brain metastasis were enrolled. Female to male ratio was 0.65 and median age at diagnosis of NSCLC was 64 years (range, 30-90). 54 patients had a solitary brain metastasis and 76 patients had more than 10 lesions. Supratentorial, infratentorial and both locations were 106, 17, and 91 patients, respectively. 116 patients (54%) had symptoms associated with brain metastasis at the diagnosis of brain metastasis. Radiation only, radiosurgery, craniotomy with whole brain radiotherapy (WBRT), and supportive care were given for brain metastasis in 111 (52%), 10 (5%), 13 (6%) and 61 (29%) patients, respectively. Overall survival (OS) was associated with age, treatment modality, histology, egfr mutation. Median OS of Radiation only, radiosurgery, craniotomy with WBRT, and supportive care was 13, 15, 15 and 9 months, respectively (P-value 0.044). Median OS of adenocarcinoma and squamous cell carcinoma was 15 and 4 months, respectively (P-value &lt;0.05). Median OS of egfr mutation and wild type was 18 and 9 months, respectively (P-value 0.016). The number and location of brain metastasis, symptoms and sex were not associated with OS Serial brain imaging was performed in 99 patients. 61 out of them (62%) developed shrinkage of brain metastasis (response group). Median OS of response and non-response group were 23 and 17 months (p-value 0.618). Age is significantly associated with response of brain metastasis to the institution’s best treatment (p-value 0.047). Interestingly, 3 patients developed complete remission of brain metastasis following WBRT and chemotherapy. The response duration was 431, 390, 641 days, respectively. Our data show that the prognosis of brain metastasis primarily depends on the age of NSCLC patients rather than the number, location of brain metastasis, treatment modality. Survival of NSCLC patients with brain metastasis was about 15 months despite the institution’s best treatment. The authors suggest that we should update our institution’s treatment policy and provide the latest treatments for patients.
Citation Format: Seung Ho Yang. Analysis of survival and prognostic factors for patients with non-small cell lung cancer and brain metastasis: 10-year experience in a single institution [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 A023.
Abstract B003: Causal effect of type II diabetes on prostate cancer in the East Asian population: A two-sample Mendelian randomization study
Authors: Guo Zhongyi 
Published: January 2023

Abstract
Type II diabetes, a metabolic disease, and prostate cancer are prevalent diseases in the elderly population. Whether type II diabetes has an association with prostate cancer has not been thoroughly studied. Limited research has been performed from a perspective of genetic level, especially among non-European populations. In this study, we used a two-sample Mendelian randomization (MR) approach to evaluate the causal effect between type II diabetes as an exposure and prostate cancer as an outcome in the East Asian population. For type II diabetes, we used 174 risk loci identified in a meta-analysis of 77,418 cases and 356,122 controls from 23 East Asian Genome-wide Association Studies (GWAS). For prostate cancer, summary statistics were extracted from the GWAS from BioBank Japan using 5,408 cases and 103,939 controls. We performed two-sample Mendelian randomization with the inverse variance weighted method while using MR Egger and weighted median methods as sensitivity analysis. For type II diabetes risk SNPs not directly present in the prostate cancer GWAS, we identified proxy SNPs in linkage disequilibrium (LD, r2  &gt;  0.8) using the 1000 genome project. We used P-value &lt; 0.05 as a threshold to determine statistical significance. Based on 152 out of 174 SNPs of type II diabetes in the East Asian population, we found that type II diabetes had a significant negative causal effect on prostate cancer [Odds Ratio (OR) = 0.76, 95% Confidence Interval (CI): 0.76 - 0.89, P = 2.26 x 10-6]. Results from sensitivity analysis using other weighting methods provided similar results. In conclusion, we observed an inverse relationship between type II diabetes and prostate cancer among the East Asian population. Patients with diabetes may have a lower risk of prostate cancer due to a reduced level of insulin and testosterone. To validate this association, further research is needed on those hormones and prostate cancer risk at the metabolic level.
Citation Format: Zhongyi Guo. Causal effect of type II diabetes on prostate cancer in the East Asian population: A two-sample Mendelian randomization study [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 B003.
Abstract B008: Autoimmune disease and the risk of anal cancer in the U.S. elderly population
Authors: Song Minkyo , Engels Eric A. , Clarke Megan A. , Kreimer Aimée R. , Shiels Meredith S. 
Published: January 2023

Abstract
Background: Recently, anal squamous cell carcinoma (SCC) has increased rapidly over time, particularly among older women. As immunosuppression is associated with increased anal cancer risk, a parallel increase in autoimmune conditions may be contributing to this rising trend. Methods: We conducted a population-based case-control study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database (years 2000-2017). Cases were individuals with first anal SCC diagnosed in SEER registries (N=4,505) and 199,566 cancer-free controls from a 5% random sample of Medicare beneficiaries. Using logistic regression, we calculated odds ratios (OR) and 95% confidence intervals (95%CI) for associations with 47 autoimmune conditions identified via Medicare claims. Models were adjusted for age (continuous), sex, race (white, others), year of selection (quartiles), average number of physician claims per year (quartiles), medicare coverage months (quartiles) and smoking status. The false discovery rate was used to correct for multiple comparisons. Results: 18% of cases and 15% of controls had any autoimmune condition diagnosed. Having any autoimmune condition was associated with an increased risk of anal SCC (OR 1.12, 95%CI 1.03-1.22). The strongest risk estimates were for sarcoidosis (OR 1.97, 95%CI 1.22-3.19), followed by systemic lupus erythematosus (1.86, 1.38-2.52) and psoriasis (1.31, 1.08-1.58). Stratified by sex, only women showed significant associations for systemic lupus erythematosus (OR 2.05, 95%CI 1.51-2.78) and men with psoriasis (1.72, 1.25-2.35) and polymyalgia rheumatica (0.33, 0.12-0.89). Conclusion: To date, this is the largest study of anal SCC exploring its association with autoimmunity, especially in this understudied old population. We report a weak to moderately increased risk of certain autoimmune diseases with anal SCC. Some associations differed by sex. Impact/Significance: Understanding the mechanism by which autoimmune diseases increase cancer anal cancer risk may guide better prevention and treatment strategies. Given the rarity of these conditions and their moderate associations with anal cancer, clinical diagnosis of autoimmune diseases cannot explain the rising trend in anal cancer. Future studies are warranted in addressing the underdiagnosis of these autoimmune conditions to better quantify the burden.
Citation Format: Minkyo Song, Eric A. Engels, Megan A. Clarke, Aimée R. Kreimer, Meredith S. Shiels. Autoimmune disease and the risk of anal cancer in the U.S. elderly population [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 B008.
Abstract B010: Association between temporal muscle thickness and overall survival in non-small cell lung cancer patients with brain metastasis
Authors: Yang Seung Ho , Kim Young Il , Kim Hyun Ho , Shim Byoung Yong 
Published: January 2023

Abstract
Temporal muscle thickness (TMT) has recently been suggested as a novel biomarker of sarcopenia in head and neck malignancies. However, few studies have evaluated TMT as a prognostic marker in patients with brain metastasis. This study investigated the association of TMT with overall survival (OS) in non-small cell lung cancer (NSCLC) patients with brain metastasis. The records of all NSCLC patients with brain metastasis between 2009 and 2018 at St. Vincent’s Hospital were reviewed retrospectively. A total of 221 patients met our eligibility criteria. In the group with TMT thicker than the median, OS was longer than the group with TMT thinner than the median (240 days versus 139 days, p = 0.014). In multivariate analysis, the thicker TMT group had longer survival (HR 0.73 CI 0.56–0.96, p = 0.024). Male (HR 1.58 CI 1.19–2.09, p = 0.002) and older age (≥ 65 years) (HR 2.05 CI 1.53–2.74, p &lt; 0.001) also showed statistical significance. We also performed subgroup analysis in older patients (≥ 65 years). In this subgroup of 107 patients, the thicker TMT group also showed longer OS than the thinner TMT group (209 days versus 82 days, p = 0.009). Our findings suggest that TMT can be a useful biomarker for OS in NSCLC patients with brain metastasis.
Citation Format: Seung Ho Yang, Young Il Kim, Hyun Ho Kim, Byoung Yong Shim. Association between temporal muscle thickness and overall survival in non-small cell lung cancer patients with brain metastasis [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 B010.
Abstract B016: Aberrant age-related methylation leads to tumor predisposition in colorectal organoids
Authors: Petkovich Daniel A. , Powers Rachael , Tao Yong , Kang Byunghak , Patel Nibedita , Gabrielson Kathy , Cabo Rafael de , Baylin Stephen B. , Easwaran Hariharan P. 
Published: January 2023

Abstract
Aging is one of the greatest risk factors for cancers, and epigenetic changes involving DNA methylation show close similarities during age-related cellular processes and tumor development. We have shown orthogonal relationships between the accrual of aberrant DNA methylation changes associated with cell division cycles during senescence and transformation. Consequently, we have hypothesized that while both senescent and proliferative aging cells coexist in the same tissues, the risk for cancer most likely comes from, and due to, epigenetic changes occurring in the latter, long-term, self-renewing cells. Using colon organoid models, we have studied the importance of genes undergoing DNA methylation mediated silencing during aging and their role in predisposing to tumorigenesis. Analyses of the in vivo and ex vivo aging-associated epigenetic/expression changes indicate the importance of age-related aberrant methylation in tumor promoting states.
Citation Format: Daniel A. Petkovich, Rachael Powers, Yong Tao, Byunghak Kang Nibedita Patel, Kathy Gabrielson, Rafael de Cabo, Stephen B. Baylin, Hariharan P. Easwaran. Aberrant age-related methylation leads to tumor predisposition in colorectal organoids [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 B016.