bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of vibration casting on the properties and microstructure of aluminium alloy castings
Authors: Buch Vyomesh , Oza Ankit D. , Kumar Manoj , Gupta Manish , Midha Shuchi
Published: February 2024

This research focuses on investigating the impact of mechanical vibration on the solidification process. Previous studies have indicated that solidification plays a crucial role in enhancing the mechanical properties of materials. By incorporating mechanical vibration technology into the solidification process, the quality of castings can be improved by achieving a more uniform microstructure and reducing grain size. In today’s industrial landscape, striving for excellence involves minimising casting defects to zero and enhancing mechanical characteristics. To comprehend the enhancement in microstructure and mechanical properties of castings, this experimental study examines the influence of mechanical mould vibration on the solidification of A356 alloy. The casting process involves a frequency of 50[Formula: see text]Hz. To evaluate the effect of vibration during casting, a comparison is made between a casting without mould vibration and its corresponding mechanical properties. The experimental results clearly demonstrate that employing a vibrating mould during casting leads to grain refinement and a significant improvement in hardness when compared to castings produced without the utilisation of a vibrating mould.
Optimal Treatment Strategies for Critical Patients with Deep Reinforcement Learning
Authors: Job Simi , Tao Xiaohui , Li Lin , Xie Haoran , Cai Taotao , Yong Jianming , Li Qing
Published: February 2024

Personalized clinical decision support systems are increasingly being adopted due to the emergence of data-driven technologies, with this approach now gaining recognition in critical care. The task of incorporating diverse patient conditions and treatment procedures into critical care decision-making can be challenging due to the heterogeneous nature of medical data. Advances in Artificial Intelligence (AI), particularly Reinforcement Learning (RL) techniques, enables the development of personalized treatment strategies for severe illnesses by using a learning agent to recommend optimal policies. In this study, we propose a Deep Reinforcement Learning (DRL) model with a tailored reward function and an LSTM-GRU-derived state representation to formulate optimal treatment policies for vasopressor administration in stabilizing patient physiological states in critical care settings. Using an ICU dataset and the Medical Information Mart for Intensive Care (MIMIC-III) dataset, we focus on patients with Acute Respiratory Distress Syndrome (ARDS) that has led to Sepsis, to derive optimal policies that can prioritize patient recovery over patient survival. Both the DDQN (
RepDRL-DDQN
) and Dueling DDQN (
RepDRL-DDDQN
) versions of the DRL model surpass the baseline performance, with the proposed model’s learning agent achieving an optimal learning process across our performance measuring schemes. The robust state representation served as the foundation for enhancing the model’s performance, ultimately providing an optimal treatment policy focused on rapid patient recovery.
Chimeric Antigen Receptor‐T (CAR‐T) Cells as “Living Drugs”: A Clinical Pharmacist Perspective
Authors: Murnane Ciara , Gardiner Nicola , Crehan Olga , Bacon Christopher L. , McHugh Ruth , Gilmer John F. , Mantalaris Athanasios , Panoskaltsis Nicki
Published: February 2024

Background. Chimeric antigen receptor (CAR) T cell therapy, a “living drug” immunotherapy, harnesses the power of T‐cells from a patient (autologous) or healthy donor (allogeneic) to target and kill cancer cells and has shown unprecedented outcomes in patients with relapsed and refractory malignancies. Treatment with CAR‐T cells requires the application of unique skillsets in recognised specialist centres for successful outcomes and requires management by the multidisciplinary team incorporating the specialist pharmacist. Method. A multimodal research strategy was employed for this literature review whereby PubMed, Google Scholar, Embase, Stella Library Search, EMA website, and EBMT website were sources of information. The search was limited from 2020 onwards with key terms referring to CAR‐T cell therapy. Results and Discussion. There are six CAR‐T cell products currently approved by the European Medicines Agency (EMA) and Food and Drug Administration (FDA) which target haematological malignancies with abundant clinical trials underway exploring new and improved CAR designs and antigen targets. As CAR‐T cell therapy is an advanced therapy medicinal product (ATMP), there is need for an extensive regulatory framework underpinning its safety and efficacy. The clinical pharmacist plays an integral role in the provision of safe and effective CAR‐T cell therapy including governance, operational and clinical aspects of treatment. Pharmacists may also be involved through provision of “Qualified Person” (QP) expertise in clinical trials and for release within hospitals under certain circumstances. There is a need for harmonised and accessible guidance on the clinical delivery of ATMPs such as CAR‐T cells, with fully delineated responsibilities of pharmacists involving the oversight and supervision of CAR‐T cell treatment. Conclusion. There is an unmet need to provide suitable and applicable literature for clinical pharmacists who are involved in the delivery of CAR‐T cells. We have provided an overview of T‐cell biology and an explanation of CAR‐T cell design and the biomanufacturing process. We reviewed the complex and multifaceted treatment cycle requiring considerable logistics, and described the involvement of the clinical pharmacist in each part of this cycle from patient selection to postinfusion care. Finally, we look to the challenges and future opportunities that will require the involvement of the clinical pharmacist.
Factors Contributing to Time-Wasting Activities among Palestinian Nurses: A Cross-Sectional Study
Authors: Zyoud Raj’a Nayef
Published: February 2024

Background. Nurses face significant challenges as they attempt to manage an increasing number of complex responsibilities within limited time frames. This article explores the factors contributing to time-wasting behaviors among nurses in Palestine and emphasizes the significance of effective time-management skills in nursing practice. Methods. Surveys were collected from a total of 714 nurses working in multiple healthcare facilities located in the north of the West Bank, Palestine. An 11-item time-wasting scale was developed and validated. Factors influencing time-wasting behaviors among nurses were then investigated using multiple linear regression in SPSS version 25. Results. Attending time management courses significantly reduced time-wasting behaviors. Additionally, factors such as age, gender, and educational level did not appear to correlate with time-wasting behaviors. However, workplace, type of organization, and attendance of time management courses did impact nurses’ time management skills. Conclusion. This article underscores the importance of time management skills in nursing practice. Inefficient time management can have detrimental effects on patient care and nursing outcomes. To mitigate these challenges, healthcare institutions and nursing education programs should prioritize time management training for nurses.
Supplementary Table S4 from Osimertinib Covalently Binds to CD34 and Eliminates Myeloid Leukemia Stem/Progenitor Cells
Authors: Xia Li , Liu Jie-Yang , Yang Meng-Ying , Zhang Xue-Hong , Jiang Yue , Yin Qian-Qian , Luo Chen-Hui , Liu Hong-Chen , Kang Zhi-Jie , Zhang Cheng-Tao , Gao Bei-Bei , Zhou Ai-Wu , Cai Hai-Yan , Waller Edmund K. , Yan Jin-Song , Lu Ying
Published: February 2024

Immunoprecipitation–MS (IP–MS) analysis using antibody against CD34 in vehicle or osimertinib treated CD34+ cells purified from AML patients.
Supplementary Table S2 from Osimertinib Covalently Binds to CD34 and Eliminates Myeloid Leukemia Stem/Progenitor Cells
Authors: Xia Li , Liu Jie-Yang , Yang Meng-Ying , Zhang Xue-Hong , Jiang Yue , Yin Qian-Qian , Luo Chen-Hui , Liu Hong-Chen , Kang Zhi-Jie , Zhang Cheng-Tao , Gao Bei-Bei , Zhou Ai-Wu , Cai Hai-Yan , Waller Edmund K. , Yan Jin-Song , Lu Ying
Published: February 2024

GO and STRING analysis of regulated tyrosine-phosphorylated peptides between vehicle or osimertinib treated CD34+ cells measured by LC-MS.
Supplementary Data from Targeting Tumor Heterogeneity with Neoantigen-Based Cancer Vaccines
Authors: Pounraj Saranya , Chen Shuxiong , Ma Linlin , Mazzieri Roberta , Dolcetti Riccardo , Rehm Bernd H.A.
Published: February 2024

Supplementary Table 1
Table 1 from Deep Learning Enables Spatial Mapping of the Mosaic Microenvironment of Myeloma Bone Marrow Trephine Biopsies
Authors: Hagos Yeman Brhane , Lecat Catherine S.Y. , Patel Dominic , Mikolajczak Anna , Castillo Simon P. , Lyon Emma J. , Foster Kane , Tran Thien-An , Lee Lydia S.H. , Rodriguez-Justo Manuel , Yong Kwee L. , Yuan Yinyin
Published: February 2024

Patient characteristics: MGUS.
Supplementary Table 10 from Deep Learning Enables Spatial Mapping of the Mosaic Microenvironment of Myeloma Bone Marrow Trephine Biopsies
Authors: Hagos Yeman Brhane , Lecat Catherine S.Y. , Patel Dominic , Mikolajczak Anna , Castillo Simon P. , Lyon Emma J. , Foster Kane , Tran Thien-An , Lee Lydia S.H. , Rodriguez-Justo Manuel , Yong Kwee L. , Yuan Yinyin
Published: February 2024

Supplementary Table 10
Supplementary Data from Deep Learning Enables Spatial Mapping of the Mosaic Microenvironment of Myeloma Bone Marrow Trephine Biopsies
Authors: Hagos Yeman Brhane , Lecat Catherine S.Y. , Patel Dominic , Mikolajczak Anna , Castillo Simon P. , Lyon Emma J. , Foster Kane , Tran Thien-An , Lee Lydia S.H. , Rodriguez-Justo Manuel , Yong Kwee L. , Yuan Yinyin
Published: February 2024

Supplementary methods, tables and figures.
Supplementary Figure 1 from A Multiethnic Germline–Somatic Association Database Deciphers Multilayered and Interconnected Genetic Mutations in Cancer
Authors: Xin Junyi , Mo Zongchao , Chai Ruichao , Hua Wei , Wang Jiguang
Published: February 2024

Supplementary Figure 1. Summary of somatic alteration-associated SNPs (P ≤ 0.001) across 33 cancer types among the three ancestry populations.
Table S1-S5, Figure S1-S3 from Serial Circulating Tumor DNA Analysis with a Tumor-Naïve Next-Generation Sequencing Panel Detects Minimal Residual Disease and Predicts Outcome in Ovarian Cancer
Authors: Heo Jinho , Kim Yoo-Na , Shin Saeam , Lee Kyunglim , Lee Ji-Hyun , Lee Yong Jae , Choi Zisun , Park Jihyang , Min Seungki , Kim Sang Wun , Choi Jong Rak , Kim Sunghoon , Lee Seung-Tae , Lee Jung-Yun
Published: February 2024

Table S1-S5, Figure S1-S3
Supplementary Video S2 from Osteoclast Cancer Cell Metabolic Cross-talk Confers PARP Inhibitor Resistance in Bone Metastatic Breast Cancer
Authors: Fan Huijuan , Xu Zhanao , Yao Ke , Zheng Bingxin , Zhang Yuan , Wang Xuxiang , Zhang Tengjiang , Li Xuan , Hu Haitian , Yue Bin , Hu Zeping , Zheng Hanqiu
Published: February 2024

Supplementary Video S2 is related to Figure 5 (Olaparib-only group).
Supplementary Data from SUMOylation-Driven mRNA Circularization Enhances Translation and Promotes Lymphatic Metastasis of Bladder Cancer
Authors: Zhao Yue , Chen Jiancheng , Zheng Hanhao , Luo Yuming , An Mingjie , Lin Yan , Pang Mingrui , Li Yuanlong , Kong Yao , He Wang , Lin Tianxin , Chen Changhao
Published: February 2024

Figure S8
Supplementary Data from Neuronal Activity Promotes Glioma Progression by Inducing Proneural-to-Mesenchymal Transition in Glioma Stem Cells
Authors: Guo Xiaofan , Qiu Wei , Wang Chaochao , Qi Yanhua , Li Boyan , Wang Shaobo , Zhao Rongrong , Cheng Bo , Han Xiao , Du Hao , Gao Zijie , Pan Ziwen , Zhao Shulin , Li Gang , Xue Hao
Published: February 2024

Figure S11. A-NDEs reduced the m6A level in GSCs
Data from A Multiethnic Germline–Somatic Association Database Deciphers Multilayered and Interconnected Genetic Mutations in Cancer
Authors: Xin Junyi , Mo Zongchao , Chai Ruichao , Hua Wei , Wang Jiguang
Published: February 2024

Abstract
Inherited germline and acquired somatic alterations can both promote human tumor development. Elucidating the cooperation between somatic and germline genetic alterations that drive tumorigenesis could help inform precision cancer prevention and treatment strategies. Here, leveraging genomic genotyping and sequencing data from 9,029 patients with cancer with European, East Asian, and African ancestry, we performed a pan-cancer analysis to evaluate the associations between germline SNPs and somatic alterations, including single-nucleotide variant and small insertion/deletion mutations, copy-number variation, tumor mutational burden, and mutational signatures. Genome-wide significant germline–somatic pairs were abundant, and most of the associations were observed in one cancer type and one ancestry group. A user-friendly interactive Multiethnic Germline–Somatic Association (MGSA) database (http://wanglab-hkust.cn:3838/MGSA/) was developed, which can be used to query, browse, and download the results of the association analyses. Moreover, the MGSA database offers additional survival analysis and functional annotation. Together, this work provides a resource for uncovering the clinical and biological roles of associations between germline variants and somatic alterations in human cancer.
Significance:
Comprehensive analysis of connections between germline variants and somatic events in cancer offers a resource for investigating the functional significance of genetic mutations and exploring genetic factors contributing to racial disparities.
Supplementary Figure 2 from Modulating Gut Microbiota Prevents Anastomotic Leak to Reduce Local Implantation and Dissemination of Colorectal Cancer Cells after Surgery
Authors: Hajjar Roy , Oliero Manon , Fragoso Gabriela , Ajayi Ayodeji Samuel , Alaoui Ahmed Amine , Vennin Rendos Hervé , Calvé Annie , Cuisiniere Thibault , Gerkins Claire , Thérien Sophie , Taleb Nassima , Dagbert François , Sebajang Herawaty , Loungnarath Rasmy , Schwenter Frank , Ratelle Richard , Wassef Ramses , De Broux Eric , Richard Carole , Santos Manuela M.
Published: February 2024

Supplementary Figure 2. Parabacteroides goldsteinii kh35 activates PPAR-y in vitro.
Table S6 from Clinical and Immunologic Features of Germline Pathogenic Variant–Positive Patients with Melanoma
Authors: Shen Alan , Arbesman Michelle , Lodha Roshan , Rayman Patricia , Bungo Brandon , Ni Ying , Chan Timothy , Gastman Brian , Ko Jennifer , Diaz-Montero C. Marcela , Arbesman Joshua , Funchain Pauline
Published: February 2024

Germline variants in TCGA vs manuscript cohort.
Table S3 from Clinical and Immunologic Features of Germline Pathogenic Variant–Positive Patients with Melanoma
Authors: Shen Alan , Arbesman Michelle , Lodha Roshan , Rayman Patricia , Bungo Brandon , Ni Ying , Chan Timothy , Gastman Brian , Ko Jennifer , Diaz-Montero C. Marcela , Arbesman Joshua , Funchain Pauline
Published: February 2024

Representativeness of study participants.
Supplemental Figure S1 from Aneuploidy Landscape in Precursors of Ovarian Cancer
Authors: Wang Yeh , Douville Christopher , Chien Yen-Wei , Wang Brant G. , Chen Chi-Long , Pinto Andre , Smith Saron Ann , Drapkin Ronny , Chui M. Herman , Numan Tricia , Vang Russell , Papadopoulos Nickolas , Wang Tian-Li , Shih Ie-Ming
Published: February 2024

Representative images of MT-CO1 loss regions and phenotype after MT-CO1 knockdown.
Arm B count matrices 4 from PD-1 Blockade Induces Reactivation of Nonproductive T-Cell Responses Characterized by NF-κB Signaling in Patients with Pancreatic Cancer
Authors: Ali Lestat R. , Lenehan Patrick J. , Cardot-Ruffino Victoire , Dias Costa Andressa , Katz Matthew H.G. , Bauer Todd W. , Nowak Jonathan A. , Wolpin Brian M. , Abrams Thomas A. , Patel Anuj , Clancy Thomas E. , Wang Jiping , Mancias Joseph D. , Reilley Matthew J. , Stucky Chee-Chee H. , Bekaii-Saab Tanios S. , Elias Rawad , Merchant Nipun , Slingluff Craig L. , Rahma Osama E. , Dougan Stephanie K.
Published: February 2024

Arm B count matrices
Supplementary Table S5 from Phase I Study of Elraglusib (9-ING-41), a Glycogen Synthase Kinase-3β Inhibitor, as Monotherapy or Combined with Chemotherapy in Patients with Advanced Malignancies
Authors: Carneiro Benedito A. , Cavalcante Ludimila , Mahalingam Devalingam , Saeed Anwaar , Safran Howard , Ma Wen Wee , Coveler Andrew L. , Powell Steven , Bastos Bruno , Davis Elizabeth , Sahai Vaibhav , Mikrut William , Longstreth James , Smith Sheri , Weisskittel Taylor , Li Hu , Borden Brittany A. , Harvey R. Donald , Sahebjam Solmaz , Cervantes Andrés , Koukol Austin , Mazar Andrew P. , Steeghs Neeltje , Kurzrock Razelle , Giles Francis J. , Munster Pamela
Published: February 2024

PK time points
Supplementary Table S4 from Phase I Study of Elraglusib (9-ING-41), a Glycogen Synthase Kinase-3β Inhibitor, as Monotherapy or Combined with Chemotherapy in Patients with Advanced Malignancies
Authors: Carneiro Benedito A. , Cavalcante Ludimila , Mahalingam Devalingam , Saeed Anwaar , Safran Howard , Ma Wen Wee , Coveler Andrew L. , Powell Steven , Bastos Bruno , Davis Elizabeth , Sahai Vaibhav , Mikrut William , Longstreth James , Smith Sheri , Weisskittel Taylor , Li Hu , Borden Brittany A. , Harvey R. Donald , Sahebjam Solmaz , Cervantes Andrés , Koukol Austin , Mazar Andrew P. , Steeghs Neeltje , Kurzrock Razelle , Giles Francis J. , Munster Pamela
Published: February 2024

Dose-escalation levels part 2
Supplementary Figure S9 from Phase I Study of Elraglusib (9-ING-41), a Glycogen Synthase Kinase-3β Inhibitor, as Monotherapy or Combined with Chemotherapy in Patients with Advanced Malignancies
Authors: Carneiro Benedito A. , Cavalcante Ludimila , Mahalingam Devalingam , Saeed Anwaar , Safran Howard , Ma Wen Wee , Coveler Andrew L. , Powell Steven , Bastos Bruno , Davis Elizabeth , Sahai Vaibhav , Mikrut William , Longstreth James , Smith Sheri , Weisskittel Taylor , Li Hu , Borden Brittany A. , Harvey R. Donald , Sahebjam Solmaz , Cervantes Andrés , Koukol Austin , Mazar Andrew P. , Steeghs Neeltje , Kurzrock Razelle , Giles Francis J. , Munster Pamela
Published: February 2024

Progression-Free Survival (A) and Overall Survival (B) with Elraglusib Monotherapy
Data from Selective DNA-PK Inhibition Enhances Chemotherapy and Ionizing Radiation Activity in Soft-Tissue Sarcomas
Authors: Laroche-Clary Audrey , Josensi Coralie , Derieppe Marie-Alix , Belhomme Sarah , Vendrely Véronique , Perret Raul , Cadogan Elaine , Italiano Antoine
Published: February 2024

AbstractPurpose:
Patients with advanced soft-tissue sarcomas (STS) exhibit a poor prognosis and have few therapeutic options. DNA-dependent protein kinase (DNA-PK) catalytic subunit is a multifunctional serine–threonine protein kinase that plays a crucial role in DNA double-strand damage repair via nonhomologous end joining.
Experimental Design:
To investigate the therapeutic potential of DNA-PK targeting in STS, we first evaluated the prognostic value of DNA-PK expression in two large cohorts of patients with STS. We then used the potent and selective DNA-PK inhibitor AZD7648 compound to investigate the antitumor effect of the pharmacologic inhibition of DNA-PK in vitro via MTT, apoptosis, cell cycle, and proliferation assays. In vivo studies were performed with patient-derived xenograft models to evaluate the effects of AZD7648 in combination with chemotherapy or ionizing radiation on tumor growth. The mechanisms of sensitivity and resistance to DNA-PK inhibition were investigated by using a genome-wide CRISPR-Cas9 positive screen.
Results:
DNA-PK overexpression is significantly associated with poor prognosis in patients with sarcomas. Selective pharmacologic inhibition of DNA-PK strongly synergizes with radiation- and doxorubicin-based regimen in sarcoma models. By using a genome-wide CRISPR-Cas9 positive screen, we identified genes involved in sensitivity to DNA-PK inhibition.
Conclusions:
DNA-PK inhibition deserves clinical investigation to improve response to current therapies in patients with sarcoma.
Supplementary figure 6 from Design and Evaluation of Phosphonamidate-Linked Exatecan Constructs for Highly Loaded, Stable, and Efficacious Antibody–Drug Conjugates
Authors: Schmitt Saskia , Machui Paul , Mai Isabelle , Herterich Sarah , Wunder Swetlana , Cyprys Philipp , Gerlach Marcus , Ochtrop Philipp , Hackenberger Christian P.R. , Schumacher Dominik , Helma Jonas , Vogl Annette M. , Kasper Marc-André
Published: February 2024

Exatecan, DXd, Enhertu and trastuzumab-LP5 induce S phase and G2/M arrest. Cell cycle arrest induced by exatecan, DXd, trastuzumab-LP5 DAR 8 and Enhertu. HER2-positive cells were treated for indicated time points and concentrations of respective free payloads and ADCs. Afterwards, permeabilized cells were stained with propidium iodide (PI) and analyzed by flow cytometry. (A) Flow cytometric histogram of PI-stained untreated SKBR-3 cells or cells treated for 48 hours with 20 nM or 0.2 nM trastuzumab-LP5 DAR 8 ADC, showing concentration-dependent induction of S phase or G2/M arrest. (B) SKBR-3 cells were treated for 48 hours with indicated concentrations of free exatecan or trastuzumab-LP5 DAR 8 ADC. (C) HER2-positive SKBR-3 and N-87 cells were treated for indicated time points with 20 nM of by exatecan, DXd, trastuzumab-LP5 DAR 8 and Enhertu. Bar graphs show % of cells in S, G2/M G0/G1 and sub G0 (apoptotic) phase. Graphs show means of n = 2 ± SEM.
Additional experimental procedures from Design and Evaluation of Phosphonamidate-Linked Exatecan Constructs for Highly Loaded, Stable, and Efficacious Antibody–Drug Conjugates
Authors: Schmitt Saskia , Machui Paul , Mai Isabelle , Herterich Sarah , Wunder Swetlana , Cyprys Philipp , Gerlach Marcus , Ochtrop Philipp , Hackenberger Christian P.R. , Schumacher Dominik , Helma Jonas , Vogl Annette M. , Kasper Marc-André
Published: February 2024

General information on the experiments and additional experimental procedures.
Supplementary Figure S8-1 from Novel Methionine Aminopeptidase 2 Inhibitor M8891 Synergizes with VEGF Receptor Inhibitors to Inhibit Tumor Growth of Renal Cell Carcinoma Models
Authors: Friese-Hamim Manja , Ortiz Ruiz Maria J. , Bogatyrova Olga , Keil Marina , Rohdich Felix , Blume Beatrix , Leuthner Birgitta , Czauderna Frank , Hahn Diane , Jabs Julia , Jaehrling Frank , Heinrich Timo , Kellner Roland , Chan Katherine , Tong Amy H.Y. , Wienke Dirk , Moffat Jason , Blaukat Andree , Zenke Frank T.
Published: February 2024

Body weight curves of Caki-1 ccRCC xenograft-bearing mice treated with vehicle or M8891 (10, 25, 50 mg/kg twice daily, per os) as monotherapy
Supplementary Figure S5-3 from Novel Methionine Aminopeptidase 2 Inhibitor M8891 Synergizes with VEGF Receptor Inhibitors to Inhibit Tumor Growth of Renal Cell Carcinoma Models
Authors: Friese-Hamim Manja , Ortiz Ruiz Maria J. , Bogatyrova Olga , Keil Marina , Rohdich Felix , Blume Beatrix , Leuthner Birgitta , Czauderna Frank , Hahn Diane , Jabs Julia , Jaehrling Frank , Heinrich Timo , Kellner Roland , Chan Katherine , Tong Amy H.Y. , Wienke Dirk , Moffat Jason , Blaukat Andree , Zenke Frank T.
Published: February 2024

Peptide sequencing by MS fragmentation: the amino acid sequence identified both peptides as N-terminal tryptic peptide of elongation factor 1 alpha-1 (EF1a-1; UniProtKB - P68104).
Supplementary Figure S2-2 from Novel Methionine Aminopeptidase 2 Inhibitor M8891 Synergizes with VEGF Receptor Inhibitors to Inhibit Tumor Growth of Renal Cell Carcinoma Models
Authors: Friese-Hamim Manja , Ortiz Ruiz Maria J. , Bogatyrova Olga , Keil Marina , Rohdich Felix , Blume Beatrix , Leuthner Birgitta , Czauderna Frank , Hahn Diane , Jabs Julia , Jaehrling Frank , Heinrich Timo , Kellner Roland , Chan Katherine , Tong Amy H.Y. , Wienke Dirk , Moffat Jason , Blaukat Andree , Zenke Frank T.
Published: February 2024

HUVEC tube formation assay
Supplementary Figure S2-1 from Novel Methionine Aminopeptidase 2 Inhibitor M8891 Synergizes with VEGF Receptor Inhibitors to Inhibit Tumor Growth of Renal Cell Carcinoma Models
Authors: Friese-Hamim Manja , Ortiz Ruiz Maria J. , Bogatyrova Olga , Keil Marina , Rohdich Felix , Blume Beatrix , Leuthner Birgitta , Czauderna Frank , Hahn Diane , Jabs Julia , Jaehrling Frank , Heinrich Timo , Kellner Roland , Chan Katherine , Tong Amy H.Y. , Wienke Dirk , Moffat Jason , Blaukat Andree , Zenke Frank T.
Published: February 2024

Representative photomicrographs of HUVEC tube formation after treatment with M8891
Figure S7 from Effects of Combined Therapeutic Targeting of AXL and ATR on Pleural Mesothelioma Cells
Authors: Hirai Soichi , Yamada Tadaaki , Katayama Yuki , Ishida Masaki , Kawachi Hayato , Matsui Yohei , Nakamura Ryota , Morimoto Kenji , Horinaka Mano , Sakai Toshiyuki , Sekido Yoshitaka , Tokuda Shinsaku , Takayama Koichi
Published: February 2024

Figure S7
Supplementary Figure S11-1 from Novel Methionine Aminopeptidase 2 Inhibitor M8891 Synergizes with VEGF Receptor Inhibitors to Inhibit Tumor Growth of Renal Cell Carcinoma Models
Authors: Friese-Hamim Manja , Ortiz Ruiz Maria J. , Bogatyrova Olga , Keil Marina , Rohdich Felix , Blume Beatrix , Leuthner Birgitta , Czauderna Frank , Hahn Diane , Jabs Julia , Jaehrling Frank , Heinrich Timo , Kellner Roland , Chan Katherine , Tong Amy H.Y. , Wienke Dirk , Moffat Jason , Blaukat Andree , Zenke Frank T.
Published: February 2024

Body weight curves of RCC PDX model RXF-2264-bearing mice treated with vehicle, M8891 (100 mg/kg, daily, per os), sunitinib (40 mg/kg, daily, per os), or the combination are shown
Figure S8 from CD38 x ICAM-1 Bispecific Antibody Is a Novel Approach for Treating Multiple Myeloma and Lymphoma
Authors: Chen Xiaocheng , Wong Oi Kwan , Reiman Lauren , Sherbenou Daniel W. , Post Leonard
Published: February 2024

FACS analysis of HuT-78 cells
Figure S10 from CD38 x ICAM-1 Bispecific Antibody Is a Novel Approach for Treating Multiple Myeloma and Lymphoma
Authors: Chen Xiaocheng , Wong Oi Kwan , Reiman Lauren , Sherbenou Daniel W. , Post Leonard
Published: February 2024

FACS and ADCC with or without Lenalidomide on NAMALWA cells
Figure S2 from SKP2 Knockout in Rb1/p53–Deficient Mouse Models of Osteosarcoma Induces Immune Infiltration and Drives a Transcriptional Program with a Favorable Prognosis
Authors: Ferrena Alexander , Wang Jichuan , Zhang Ranxin , Karadal-Ferrena Burcu , Al-Hardan Waleed , Singh Swapnil , Borjihan Hasibagan , Schwartz Edward L. , Zhao Hongling , Oktay Maja H. , Yang Rui , Geller David S. , Hoang Bang H. , Zheng Deyou
Published: February 2024

Gene set enrichment analysis (GSEA) indicates upregulation of interferon response and downregulation of unfolded protein response in TKO.
Abstract A012: Molecular profiling of neoductgenesis in early stage breast cancer for the development of novel diagnostic biomarkers
Authors: Lehtinen Laura , Koskinen Leena , Peurla Markus , Huotari Emilia , Kauko Otto , Dean Peter , Hartiala Pauliina , Boström Pia , Peuhu Emilia
Published: February 2024

Ductal carcinoma in situ (DCIS) is the most common precancerous finding in mammography screens. DCIS generally has a good prognosis, and only 20-25% of the cases progress to invasive breast carcinoma (IBC) even if left untreated. Breast pathologists and radiologists have suggested that there are currently more than one kind of DCIS under the same diagnosis. A subset of DCIS cases with reduced survival rate are associated with casting-type calcifications that can be histologically detected within closely packed, contorted, newly formed ducts, a phenomenon called neoductgenesis. Tumors with neoductgenesis are often erroneously diagnosed as DCIS, while in fact, they are associated with higher degree of metastasis and should be considered invasive carcinomas. This tumor category currently lacks specific histopathological markers and the biological processes leading to metastasis via neoductgenesis remain poorly characterised. To reveal new information of this breast tumor type, we are currently conducting comprehensive characterization of FFPE tissue samples of DCIS cases with and without neoductgenesis using imaging mass cytometry analysis and immunohistochemistry of specific tumor areas. Preliminary results on immunofluorescence staining suggest that neoductgenesis is associated with changes in the expression of specific myoepithelial marker proteins compared to areas with pure DCIS. In addition, we are analysing the three-dimensional ductal architecture of these lesions. The information obtained from this study can lead to development of new diagnostic tools for the identification of early breast cancers with a higher risk of spreading. Early detection of these cases is important to ensure the effectiveness and timeliness of treatment, and at the same time to improve the patients' quality of life.

Citation Format: Laura Lehtinen, Leena Koskinen, Markus Peurla, Emilia Huotari, Otto Kauko, Peter Dean, Pauliina Hartiala, Pia Boström, Emilia Peuhu. Molecular profiling of neoductgenesis in early stage breast cancer for the development of novel diagnostic biomarkers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A012.
Abstract A042: Characterization of the hormone receptor-positive breast tumor immune microenvironment using single cell transcriptomics and multiplex immunofluorescence
Authors: Michaud Daniel , Shimada Kenichi , Zheng Kelly , Gu Cheryl , Cui Yvonne , Goldberg Jonathan , Ogayo Esther , Sorger Peter , Santagata Sandro , Mittendorf Elizabeth , Guerriero Jennifer
Published: February 2024

Hormone receptor-positive (HR+) breast tumors are the most frequently diagnosed type of breast cancer (~70%) and are characterized by the expression of the estrogen receptor and/or the progesterone receptor. HR+ breast tumors derive limited benefit from immune checkpoint therapy (ICT), which can be at least partially attributed in part, to low levels of T cell infiltration and low expression of T cell immune checkpoint molecules. In other solid tumors, targeting components of the tumor microenvironment outside of T cells have shown the ability to enhance ICT responses, however, such targets have been relatively unexplored in HR+ breast cancer. We hypothesize that there are unidentified targetable non-lymphocyte immune populations within the HR+ breast tumor microenvironment, which can be targeted to increase response to ICT. We performed paired bulk RNA sequencing and cyclic immunofluorescence (CyCIF) from untreated human HR+ tumors (n=30) as well as single-cell RNA sequencing (scRNA-seq) on a subset (N=17) of the tumors, to characterize the spatial composition of the immune infiltrate and identify gene expression profiles that correlate with T cell infiltration. We have identified tumor-associated macrophages (TAMs) as being the immune cell population most abundant in HR+ tumors by both scRNA-seq & CyCIF. We identified SPP1+ CD36+ expressing macrophages to be significantly enriched in T cell-low compared to T cell-high HR+ tumors. These SPP1+ CD36+ macrophages have been previously linked to lipid metabolism in the tumor microenvironment and we confirmed such with gene set enrichment analysis. Inversely, T cell high HR+ tumors displayed a significant enrichment of MUCL1+APOD+ macrophages expressing high levels of MHC class II molecules and enriched for gene sets relating to antigen presentation and interferon responses. Collectively, these findings put forth two populations of macrophages within HR+ tumors as novel immunotherapeutic targets for further investigation to enhance T cell responses and ICT.

Citation Format: Daniel Michaud, Kenichi Shimada, Kelly Zheng, Cheryl Gu, Yvonne Cui, Jonathan Goldberg, Esther Ogayo, Peter Sorger, Sandro Santagata, Elizabeth Mittendorf, Jennifer Guerriero. Characterization of the hormone receptor-positive breast tumor immune microenvironment using single cell transcriptomics and multiplex immunofluorescence [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A042.
Abstract A061: Grb7 is dispensible for normal development and ERBB2-driven mammary tumorigenesis, but maternal Grb7 deletion causes lactational insufficiency
Authors: Lofgren Kristopher A. , Feiszt Peter , Kenny Paraic A.
Published: February 2024

Growth factor receptor-bound 7 (Grb7) is an adaptor protein implicated in signal transduction downstream of multiple receptor tyrosine kinases, including ERBB, FGFR and PDGFR pathways. Experimental studies have implicated Grb7 in regulating cell proliferation, survival, migration, and invasion through its large repertoire of protein-protein interactions. Here, we describe the generation and characterization of a Grb7 knockout (KO) mouse. These mice are viable and fertile. A lacZ knock-in reporter was used to visualize Grb7 promoter activity patterns in adult tissues, indicating widespread Grb7 expression in glandular epithelium, the central nervous system and other tissues. The sole defect observed in these animals was a failure of Grb7 KO females to successfully raise pups to weaning age, a phenotype that was independent of both paternal and pup genotypes. These data suggest a regulatory role for Grb7 in mammary lactational physiology. Grb7 is genomically adjacent to ERBB2 and commonly co-amplified with ERBB2 in human breast cancer. This adaptor protein physically interacts with ERBB2 and has been implicated in oncogenic signal propagation to intracellular pathways. We intercrossed Grb7 KO and MMTV-Neu mice to determine whether Grb7 is required for ERBB2-driven tumorigenesis. Surprisingly, there was no difference in time to tumor detection between cohorts, indicating that Grb7 is not obligately required for ERBB2-driven tumorigenesis. In conclusion, despite a considerable body of literature suggesting key roles for Grb7 in signal transduction pathways involved in both normal and malignant processes, our analysis of Grb7 KO mice demonstrates that Grb7 is largely dispensable for both development and ERBB2-driven tumorigenesis. These data raise the possibility that other Grb family members, Grb10 and Grb14, might compensate for Grb7 loss. Accordingly, a comprehensive assessment of all Grb family members may be needed to fully clarify their physiological roles.

Citation Format: Kristopher A. Lofgren, Peter Feiszt, Paraic A. Kenny. Grb7 is dispensible for normal development and ERBB2-driven mammary tumorigenesis, but maternal Grb7 deletion causes lactational insufficiency [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A061.
Abstract A087: Morphometric analysis of the terminal ductal lobular unit architecture in human breast
Authors: Peurla Markus , Paavolainen Oona , Tammelin Ella , Sulander Suvi-Riitta , Mourao Larissa , Boström Pia , Brück Nina , Scheele Colinda LGJ , Hartiala Pauliina , Peuhu Emilia
Published: February 2024

The major lactiferous ducts of the human breast branch out and ultimately end at terminal ductal lobular units (TDLUs). These glandular structures are the source of milk upon lactation, and also the most common origin of breast cancer. Despite their functional and clinical importance, the three dimensional (3D) architecture of TDLUs has remained undetermined, largely due to their absence in rodent animal models. By utilizing recent technological advances in optical tissue clearing and microscopy, we imaged the 3D structure of healthy human breast tissue to determine whether general branching patterns or cell type specific niches exist in the TDLU. Our data demonstrate that TDLUs have a consistent shape and their branch parameters are largely comparable between different TDLUs and individuals irrespective of age or parity. Simulation of TDLU branching morphogenesis in 3D by mathematical modelling suggests that evolutionarily conserved mechanisms regulate mammary gland branching in humans and mice, despite their anatomical differences. The data also demonstrate a new level of organization within the TDLU structure identifying a main branch that dominates in bifurcation events and exhibits a more duct-like keratin expression pattern. In all, our data provide the first structural insights into 3D human breast anatomy and branching, and exemplify the power of volumetric imaging in deeper understanding of human breast biology.

Citation Format: Markus Peurla, Oona Paavolainen, Ella Tammelin, Suvi-Riitta Sulander, Larissa Mourao, Pia Boström, Nina Brück, Colinda LGJ Scheele, Pauliina Hartiala, Emilia Peuhu. Morphometric analysis of the terminal ductal lobular unit architecture in human breast [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A087.
Abstract B008: KDM4C histone demethylase connects redox balance to chromatin remodeling via histone H3 tail clipping
Authors: Li Zheqi , Peluffo Guillermo , Stevens Laura , Qiu Xintao , Seehawer Marco , Huang Xiao-Yun , Egri Shawn , Papanastasiou Malvina , Kingston Natalie , D'Santos Clive , Papachristou Eva , Nishida Jun , Evans Kyle , Seo Ji-Heui , Clement Kendell , Temko Daniel , Ekram Muhammad , Rees Matthew , Ronan Melissa , Roth Jennifer , Simeonov Anton , Kales Stephen , Rai Ganesha , Lal-Nag Madhu , Maloney David , Jadhav Ajit , Michor Franziska , Meissner Alex , Balko Justin , Carroll Jason , Freedman Matthew , Long Henry , Jaffe Jacob , Polyak Kornelia
Published: February 2024

Triple-negative breast cancer (TNBC) is a breast cancer subtype with inferior prognosis necessitating the discovery of novel therapeutic targets. In this study, we describe that KDM4C, a histone demethylase amplified and overexpressed in a subset of TNBC is a driver of TNBC tumor growth. Integrative multi-omic analysis using RNA-seq, ChIP-seq and ATAC-seq demonstrated that KDM4C inhibition triggers chromatin and transcriptomic remodeling without substantial changes of its canonical substrates H3K9me3 and H3K36me3 in TNBC breast cancer cells. Rather KDM4C loss surprisingly caused proteolytic cleavage at histone 3 N terminus (A21 site) identified by histone mass spectrometry. Protease inhibitor array pointed out cathepsin L (CTSL) as the endopeptidase mediating this procedure and CTSL proteomic interactome profiling further uncovered that grainyhead like transcription factor 2 (GRHL2) recruited CTSL to the chromatin. Metabolomic profiling showed reduced glutathione levels following KDM4C inhibition partly due to a decrease in glutamate-cysteine ligase (GCLC) triggered by CTSL-mediated histone H3 cleavage and subsequent increase in reactive oxygen species (ROS). Knockout of CTSL rescued KDM4C blockade-associated metabolic dysfunction and tumor suppression in vivo. The expression of KDM4C and GCLC correlated in TNBC and combined targeting of KDM4C and the GSH axis improved response to cisplatin in cell culture and xenograft models. Our study reveals a novel role for KDM4C in TNBC that links cellular redox regulation and epigenetics.

Citation Format: Zheqi Li, Guillermo Peluffo, Laura Stevens, Xintao Qiu, Marco Seehawer, Xiao-Yun Huang, Shawn Egri, Malvina Papanastasiou, Natalie Kingston, Clive D'Santos, Eva Papachristou, Jun Nishida, Kyle Evans, Ji-Heui Seo, Kendell Clement, Daniel Temko, Muhammad Ekram, Matthew Rees, Melissa Ronan, Jennifer Roth, Anton Simeonov, Stephen Kales, Ganesha Rai, Madhu Lal-Nag, David Maloney, Ajit Jadhav, Franziska Michor, Alex Meissner, Justin Balko, Jason Carroll, Matthew Freedman, Henry Long, Jacob Jaffe, Kornelia Polyak. KDM4C histone demethylase connects redox balance to chromatin remodeling via histone H3 tail clipping [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B008.
Abstract B011: BRCA2 haploinsufficiency induces P53 degradation in primary mammary epithelial cells – a crucial early event in breast tumor promotion
Authors: Duan Haohui , Gillis Margaret , Dillon Deboral , Garber Judy , Pathania Shailja
Published: February 2024

The presence of heterozygous germline BRCA2 mutations is associated with an increased risk of breast and ovarian cancer. In order to design effective preventative strategies, it is critical to understand early tumor promoting events that the mammary epithelial cells undergo on their way to tumorigenesis. To investigate the impact of BRCA2 heterozygosity on tumor formation, we utilized primary BRCA2mut/+ mammary epithelial cells obtained from prophylactic breast tissue of women with BRCA2 mutations. Our findings indicate that BRCA2mut/+ cells display haploinsufficiency for repairing stalled replication forks and resolving RPA32 from these sites, indicative of impaired stalled fork repair. Moreover, they exhibit defects in RAD51 recruitment to double strand break sites indicating a defective homologous recombination dependent double strand break repair efficiency. BRCA2mut/+ cells also show increased sensitivity to both replication stress and double strand break-inducing agents. Interestingly, we find that BRCA2 heterozygous cells downregulate P53 protein levels when compared to BRCA2 wild type cells, and that this downregulation is MDM2-dependent. The decreased P53 levels appear to promote the survival of BRCA2 heterozygous cells under endogenous replication stress conditions. Notably, treatment with nutlin, a P53 protein stabilizer, leads to cell death in BRCA2 heterozygous cells but not in BRCA2 wildtype cells, highlighting the sensitivity of BRCA2 heterozygous cells to endogenous P53 protein levels. Moreover, complete loss of P53 in BRCA2 heterozygous cells results in rescue of sensitivity of these cells to both replication stress and double strand break inducing agents. Furthermore, whole genome sequencing analysis of BRCA2 heterozygous cells deleted for P53 reveal DNA mutational signatures similar to those observed in BRCA2 mutant tumors, implying that loss or downregulation of P53 is an early event driving tumorigenesis in the context of BRCA2 heterozygosity. In summary, our study uncovers the significance of BRCA2 haploinsufficiency in replication stress suppression and highlights the role of P53 loss in promoting BRCA2 heterozygosity-driven cancer. These findings contribute to a better understanding of the molecular mechanisms underlying BRCA2-associated tumorigenesis and may have implications for targeted preventative therapies in the future.

Citation Format: Haohui Duan, Margaret Gillis, Deboral Dillon, Judy Garber, Shailja Pathania. BRCA2 haploinsufficiency induces P53 degradation in primary mammary epithelial cells – a crucial early event in breast tumor promotion [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B011.
Abstract B020: Pan-RAS inhibitors to treat luminal B beast cancer
Authors: Clark Geoff , Jigo Raphael , Donninger Howard , Burlison Joe , Sabo Mike , Arshad tariq , Trent John
Published: February 2024

The RAS oncoprotein has not traditionally been considered as an important driver of breast cancer due to the paucity of RAS mutations in this disease. However, RAS signaling pathways are frequently hyper-activated in breast cancers and genetic/epigenetic inactivation of RAS negative regulators (GAPs) is common. This is particularly true for Luminal B breast cancer. Luminal breast cancer makes up the majority of Breast Cancers, ~ 65% of cases. About 2/3 of these are classed as Luminal A and about 1/3 being the Luminal B class. Although current therapeutic options for luminal A (surgery, endocrine therapy) can be reasonably effective, Luminal B tumors are much more dangerous. These tumors are less sensitive to therapy in the first place and have a high frequency of relapse. Moreover, Luminal B tumors tend to occur more frequently in younger women and have a higher incidence of metastasis. One recent analysis has shown that Luminal B cancers have little better overall survival rates than the notorious triple negative breast cancers. Therefore, better therapies for Luminal B breast cancer are urgently required. One approach may be to target the hyper-active wild-type RAS oncoprotein that drives many of these Luminal B tumors. We have used in silico library screening followed by Medicinal Chemistry optimization to develop a series of novel small molecules that bind to all three main wild type RAS proteins and inhibit RAS function. We have validated the agents by using Microscale Thermophoresis binding procedures to quantify recombinant protein interaction. We used 3D growth inhibition and protein-based RAS signaling assays to quantify the biological action of the agents. Finally, we validated one of the more effective agents in vivo against a Luminal B cell line xenograft. This may be the first example of an effective anti-RAS therapy in breast cancer. It serves as proof of principal for the use of ant-RAS drugs in Luminal B disease. As basal breast cancers often exhibit loss of function of the RAS GAP called NF1, this strategy may have applications beyond Luminal B disease.

Citation Format: Geoff Clark, Raphael Jigo, Howard Donninger, Joe Burlison, Mike Sabo, tariq Arshad, John Trent. Pan-RAS inhibitors to treat luminal B beast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B020.
Abstract B055: Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance
Authors: Iqbal Mohammad A , Siddiqui Shumaila , Smith Kirk , Singh Prithvi , Kumar Bhupender , Chouaib Salem , Chandrasekaran Sriram
Published: February 2024

Metabolic heterogeneity in breast cancer has limited the deployment of metabolic therapies. To enable patient stratification, we studied global metabolic landscape of breast cancer (N>3000 combined) and identified three metabolic subtypes with increasing degrees of metabolic deregulation. M1 exhibited deregulated bile acid biosynthesis whereas M2 showed reliance on methionine pathway and M3 was found to be the most metabolically aggressive engaging fatty, nucleotide, and glucose metabolism. Extent of metabolic deregulation correlated strongly with tumor aggressiveness and patient outcome Moreover bile acid biosynthesis predicted less aggressive tumors with better prognosis while pyrimidine metabolism predicted the opposite trend. Notably this pattern was reproducible in independent datasets and in vivo tumor metabolite data. Genomic characterization of metabolic subtypes revealed TP53 mutation and MYC amplification as the strongest predictor of metabolic deregulation. Using machine learning, we identified robust and generalizable signatures that recaptured metabolic subtypes in tumors and cell lines. Surprisingly, the least deregulated M1 subtype was not found to be represented by any of the 50 cell line models analyzed. Experimental inhibition of metabolic pathways demonstrated subtype specific sensitivity and improved combinatorial efficacy of chemotherapeutic drugs. In addition, breast cancer cell lines representing metabolic subtypes revealed therapeutically relevant drugs. Taken together, this work presents metabolic stratification of breast cancer patients that may have implications in predicting patient outcome and designing precision therapies.

Citation Format: Mohammad A Iqbal, Shumaila Siddiqui, Kirk Smith, Prithvi Singh, Bhupender Kumar, Salem Chouaib, Sriram Chandrasekaran. Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B055.