bluuebunny/crossref_metadata_2025 huggingface dataset:
The Challenges of Implementing Good Health and Well‐Being During a Pandemic: A Case Study of the Behavior of Using Telemedicine Services in the Younger Generation
Authors: Parahyanti Endang , Zharifah Afiyah Tsarwat , Lazuardi Sinan Vidi
Published: November 2024

Objectives: Telemedicine has emerged as a crucial tool in addressing public health requirements, particularly during a pandemic. This aligns with the third Sustainable Development Goals (SDGs) objective of ensuring healthy lives and promoting well‐being for all ages. The current generation demonstrates a greater proficiency in modern technology, prompting researchers to investigate their views and behavior trends in telemedicine.

Methods: This research is aimed at examining the telemedicine adoption patterns of Generation Y and Generation Z by dividing them into two groups. Study Group 1 is comprised of those who have known modern technology but have yet to gain experience in using telemedicine. Meanwhile, Study Group 2 is comprised of those who had used telemedicine services. Utilizing structural equation model (SEM) analysis, this research investigates the magnitude of influence exerted by various determinants on an individual’s tendency to utilize telemedicine.

Results: Findings from both study groups indicate that younger generations have positive attitudes towards telemedicine, significantly influencing their willingness to use telemedicine. Furthermore, the level of readiness for change emerges as a crucial factor in determining the degree of affective commitment to change, continuance commitment to change, and normative commitment to change. In addition, the participants’ affective experience state significantly influences all three dimensions of commitment to change.

Conclusion: The results suggest the importance of fostering a positive and pragmatic understanding of telemedicine among young people. This can be achieved by encouraging the use of telemedicine services and fully adopting the shift to telemedicine. Therefore, it is crucial to prioritize the development of a positive view towards telemedicine, provide excellent service experiences, and promote social flexibility to attract a large user base, especially among the younger population.
Practice Variations in the Diagnosis and Treatment of Pulmonary Embolism
Authors: Thakkar Devesh , Garden Frances , Nguyen John , Ta Brenda , Hussaini Sikandar , Dobler Claudia C.
Published: November 2024

Venous thromboembolism is responsible for a significant burden of disease worldwide. Despite the publication of multiple international guidelines, anecdotal evidence suggests significant clinical variation exists in the diagnostic and management pathways of pulmonary embolism (PE). We conducted a retrospective cohort study using electronic medical records to examine clinical variation in patients admitted to a tertiary referral center in Australia with a diagnosis of PE between November 2018 and January 2020. Three hundred cases met the inclusion criteria; we found variation in rates of compression ultrasonography, acute investigation of the right ventricle, and planning of repeat imaging at specialist follow‐up. Guidelines do not address the use of compression ultrasonography in already diagnosed PE, are conflicting in their recommendation for acute investigation of the right ventricle, and recommend repeat imaging only if there are persistent symptoms at the time of specialist follow‐up. The variations we found in this study may in part be due to physician preference or due to the paucity of evidence for some of these diagnostic practices. Robust future studies are required to guide the use of these investigations in PE.
Drilling of Ti Grade‐2 Alloy Using WC Tool in Micro‐EDM and Its Multiparameter Optimization
Authors: Kebede Alemu Workie , Majumder Tanmoy , Patowari Promod Kumar , Sahoo Chinmaya Kumar
Published: November 2024

In this study, microelectrical discharge machining (μEDM) is used for drilling microholes on a thin sheet of Ti Grade 2 alloy of thickness 50 μm using a tungsten carbide (WC) microtool of diameter 470 μm. The main focus of the study is to understand the electrical and nonelectrical μEDM parameters on the accuracy, precision, and machining efficiency of drilled holes. The controllable process factors such as capacitance, voltage, tool rotation, and feed rate are considered when conducting the experiments based on a Taguchi L16 orthogonal array. The main effect and interaction contour plots have been prepared to investigate the influence of the process parameters on the response measures like material removal rate, overcut, circularity, and taper angle of the drilled holes. Analysis of variance (ANOVA) has been carried out to study the percentage contribution and significance of each process parameter on the performance measures. The micrographic images reveal the quality of the profiles and edges of the drilled holes. Further, the Overall Evaluation Criterion (OEC) is applied for multiparameter optimization.
Postshift Hand Fatigue in Emergency Service Nurses
Authors: Ulupınar Fadime , Meler Sibel , Karasu Şeyda , Ulupınar Süleyman
Published: November 2024

Objective: Hand functionality, defined as the ability to perform tasks requiring fine motor skills, is crucial for emergency service nurses as it directly affects their ability to perform tasks requiring fine motor skills, such as administering medication, operating equipment, and providing patient care. This study, therefore, aimed to investigate the effects of an 8‐h work shift on hand functionality and perceived exertion among emergency service nurses.

Method: Employing a cross‐sectional design, the study measured manual dexterity, handgrip, and pinch strength, and perceived exertion using the Minnesota Manual Dexterity Test (MMDT), Nine‐Hole Peg Test (9‐HPT), Handgrip Strength Test, Pinch Strength Test, and the Borg Rating of Perceived Exertion (RPE) Scale. Data were collected from 34 emergency service nurses both before and after their shifts.

Results: The present findings indicated significant postshift declines in manual dexterity as evidenced by the MMDT and 9‐HPT, with the former demonstrating a large effect size and the latter a small effect size. No significant changes were observed in handgrip and pinch strength. Notably, Borg RPE scores increased significantly postshift, indicating substantial perceived fatigue with a nearly perfect effect size. Correlation analyses revealed significant relationships between increased physical exertion and changes in hand dexterity and strength, underscoring the physical demands placed on nurses during typical work shifts.

Conclusions: These findings highlight the need for healthcare institutions to reassess work schedules and ergonomic practices to mitigate fatigue and preserve nurses’ hand functionality, thereby enhancing patient care and nurse well‐being. The study calls for further research to explore more comprehensive strategies aimed at reducing the occupational strain on emergency service nurses.
Supplementary Table S1 from The Genomic Landscape of Benign and Malignant Thyroid Tumors from Individuals Carrying Germline PTEN Variants Is Distinct from Sporadic Thyroid Cancers
Authors: Plitt Gilman , Brewer Takae , Yehia Lamis , Rabinowitz Laura , Griffith Christopher C. , Eng Charis
Published: November 2024

Thyroid tumor-associated genes
Supplemental Table 1 from Targeting YES1 Disrupts Mitotic Fidelity and Potentiates the Response to Taxanes in Triple-Negative Breast Cancer
Authors: Piemonte Katrina M. , Ingles Natasha N. , Weber-Bonk Kristen L. , Valentine Mitchell J. , Majmudar Parth R. , Singh Salendra , Keri Ruth A.
Published: November 2024

Methods RR_IDs
Supplemental Figure 8 from Targeting YES1 Disrupts Mitotic Fidelity and Potentiates the Response to Taxanes in Triple-Negative Breast Cancer
Authors: Piemonte Katrina M. , Ingles Natasha N. , Weber-Bonk Kristen L. , Valentine Mitchell J. , Majmudar Parth R. , Singh Salendra , Keri Ruth A.
Published: November 2024

Treatment with YES1i, paclitaxel, or the combination is non-toxic, in vivo.
Supplementary Table S1 from KHSRP Stabilizes m6A-Modified Transcripts to Activate FAK Signaling and Promote Pancreatic Ductal Adenocarcinoma Progression
Authors: Xu Zilan , Zhou Yifan , Liu Shaoqiu , Zhao Hongzhe , Chen Ziming , Li Rui , Li Mei , Huang Xudong , Deng Shuang , Zeng Lingxing , Zhao Sihan , Zhang Shaoping , He Xiaowei , Liu Ji , Xue Chunling , Bai Ruihong , Zhuang Lisha , Zhou Quanbo , Chen Rufu , Lin Dongxin , Zheng Jian , Zhang Jialiang
Published: November 2024

Supplementary Table S1
Supplemental Figure 5 from Targeting YES1 Disrupts Mitotic Fidelity and Potentiates the Response to Taxanes in Triple-Negative Breast Cancer
Authors: Piemonte Katrina M. , Ingles Natasha N. , Weber-Bonk Kristen L. , Valentine Mitchell J. , Majmudar Parth R. , Singh Salendra , Keri Ruth A.
Published: November 2024

Pharmacologically targeting YES1 induces chromosomal instability, centrosome dysfunction, and multipolar spindle formation.
Figure S5 from KHSRP Stabilizes m6A-Modified Transcripts to Activate FAK Signaling and Promote Pancreatic Ductal Adenocarcinoma Progression
Authors: Xu Zilan , Zhou Yifan , Liu Shaoqiu , Zhao Hongzhe , Chen Ziming , Li Rui , Li Mei , Huang Xudong , Deng Shuang , Zeng Lingxing , Zhao Sihan , Zhang Shaoping , He Xiaowei , Liu Ji , Xue Chunling , Bai Ruihong , Zhuang Lisha , Zhou Quanbo , Chen Rufu , Lin Dongxin , Zheng Jian , Zhang Jialiang
Published: November 2024

Figure S5 and it's legend
Supplemental Figure 1 from Targeting YES1 Disrupts Mitotic Fidelity and Potentiates the Response to Taxanes in Triple-Negative Breast Cancer
Authors: Piemonte Katrina M. , Ingles Natasha N. , Weber-Bonk Kristen L. , Valentine Mitchell J. , Majmudar Parth R. , Singh Salendra , Keri Ruth A.
Published: November 2024

Expression of SFK family members other than YES1 is not predictive of outcomes in patients with basal breast cancer.
Figure S1 from KHSRP Stabilizes m6A-Modified Transcripts to Activate FAK Signaling and Promote Pancreatic Ductal Adenocarcinoma Progression
Authors: Xu Zilan , Zhou Yifan , Liu Shaoqiu , Zhao Hongzhe , Chen Ziming , Li Rui , Li Mei , Huang Xudong , Deng Shuang , Zeng Lingxing , Zhao Sihan , Zhang Shaoping , He Xiaowei , Liu Ji , Xue Chunling , Bai Ruihong , Zhuang Lisha , Zhou Quanbo , Chen Rufu , Lin Dongxin , Zheng Jian , Zhang Jialiang
Published: November 2024

Figure S1 and it's legend
Supplementary Information from LX1 Dual Targets AR Variants and AKR1C3 in Advanced Prostate Cancer Therapy
Authors: Ning Shu , Armstrong Cameron M. , Xing Enming , Leslie Amy R. , Gao Richard Y. , Sharifi Masuda , Schaaf Zachary A. , Lou Wei , Han Xiangrui , Xu Desiree H. , Yang Rui , Cheng Jeffrey , Mohammed Shabber , Mitsiades Nicholas , Liu Chengfei , Lombard Alan P. , Wu Chun-Yi , Cheng Xiaolin , Li Pui-Kai , Gao Allen C.
Published: November 2024

Suppl. Figure 1-10, Table 1-2.
Figure S5 from Molecular Characterization and Classification of HER2-Positive Breast Cancer Inform Tailored Therapeutic Strategies
Authors: Li Yu-Wei , Dai Lei-Jie , Wu Xiang-Rong , Zhao Shen , Xu Yu-Zheng , Jin Xi , Xiao Yi , Wang Ying , Lin Cai-Jin , Zhou Yi-Fan , Fu Tong , Yang Wen-Tao , Li Ming , Lv Hong , Chen Siyuan , Grigoriadis Anita , Jiang Yi-Zhou , Ma Ding , Shao Zhi-Ming
Published: November 2024

Figure S5
Figure S3 from Molecular Characterization and Classification of HER2-Positive Breast Cancer Inform Tailored Therapeutic Strategies
Authors: Li Yu-Wei , Dai Lei-Jie , Wu Xiang-Rong , Zhao Shen , Xu Yu-Zheng , Jin Xi , Xiao Yi , Wang Ying , Lin Cai-Jin , Zhou Yi-Fan , Fu Tong , Yang Wen-Tao , Li Ming , Lv Hong , Chen Siyuan , Grigoriadis Anita , Jiang Yi-Zhou , Ma Ding , Shao Zhi-Ming
Published: November 2024

Figure S3
Supplementary Table 4 from CRISPR Screening of Transcribed Super-Enhancers Identifies Drivers of Triple-Negative Breast Cancer Progression
Authors: Lewis Michael W. , King Caitlin M. , Wisniewska Kamila , Regner Matthew J. , Coffey Alisha , Kelly Michael R. , Mendez-Giraldez Raul , Davis Eric S. , Phanstiel Douglas H. , Franco Hector L.
Published: November 2024

Differentially expressed genes from CRISPRi screen
Table S1-S4 from FOXP4 Is a Direct YAP1 Target That Promotes Gastric Cancer Stemness and Drives Metastasis
Authors: Liu Xiaoli , Chen Bonan , Xie Fuda , Wong Kit Yee , Cheung Alvin H.K. , Zhang Jinglin , Wu Qian , Fang Canbin , Hu Jintao , Wang Shouyu , Xu Dazhi , Chen Jianwu , Wang Yuzhi , Wong Chi Chun , Chen Huarong , Wu William K.K. , Yu Jun , Chan Michael W.Y. , Tsang Chi Man , Lo Kwok Wai , Tse Gary M.K. , To Ka-Fai , Kang Wei
Published: November 2024

Supplementary Table S1-S4
Supplementary Table 2 from CRISPR Screening of Transcribed Super-Enhancers Identifies Drivers of Triple-Negative Breast Cancer Progression
Authors: Lewis Michael W. , King Caitlin M. , Wisniewska Kamila , Regner Matthew J. , Coffey Alisha , Kelly Michael R. , Mendez-Giraldez Raul , Davis Eric S. , Phanstiel Douglas H. , Franco Hector L.
Published: November 2024

List of super-enhancer genomic coordinates
Supplementary Table 3 from H3K18 Lactylation Potentiates Immune Escape of Non–Small Cell Lung Cancer
Authors: Zhang Cai , Zhou Lijie , Zhang Mingyuan , Du Yue , Li Cai , Ren Huijun , Zheng Lu
Published: November 2024

Primers
Supplementary Table 2 from H3K18 Lactylation Potentiates Immune Escape of Non–Small Cell Lung Cancer
Authors: Zhang Cai , Zhou Lijie , Zhang Mingyuan , Du Yue , Li Cai , Ren Huijun , Zheng Lu
Published: November 2024

Antibodies and oligonucleotides
Figure S10 from FOXP4 Is a Direct YAP1 Target That Promotes Gastric Cancer Stemness and Drives Metastasis
Authors: Liu Xiaoli , Chen Bonan , Xie Fuda , Wong Kit Yee , Cheung Alvin H.K. , Zhang Jinglin , Wu Qian , Fang Canbin , Hu Jintao , Wang Shouyu , Xu Dazhi , Chen Jianwu , Wang Yuzhi , Wong Chi Chun , Chen Huarong , Wu William K.K. , Yu Jun , Chan Michael W.Y. , Tsang Chi Man , Lo Kwok Wai , Tse Gary M.K. , To Ka-Fai , Kang Wei
Published: November 2024

Supplementary Figure S10
Supplementary Tables from Neuroendocrine Differentiation in Prostate Cancer Requires ASCL1
Authors: Rodarte Kathia E. , Nir Heyman Shaked , Guo Lei , Flores Lydia , Savage Trisha K. , Villarreal Juan , Deng Su , Xu Lin , Shah Rajal B. , Oliver Trudy G. , Johnson Jane E.
Published: November 2024

Supplementary Tables S1-S6
Supplementary Data Figure S5 from Neuroendocrine Differentiation in Prostate Cancer Requires ASCL1
Authors: Rodarte Kathia E. , Nir Heyman Shaked , Guo Lei , Flores Lydia , Savage Trisha K. , Villarreal Juan , Deng Su , Xu Lin , Shah Rajal B. , Oliver Trudy G. , Johnson Jane E.
Published: November 2024

Genotypes of RPMA organoids and differences in metastatic burden.
Supplementary Data Figure S4 from Neuroendocrine Differentiation in Prostate Cancer Requires ASCL1
Authors: Rodarte Kathia E. , Nir Heyman Shaked , Guo Lei , Flores Lydia , Savage Trisha K. , Villarreal Juan , Deng Su , Xu Lin , Shah Rajal B. , Oliver Trudy G. , Johnson Jane E.
Published: November 2024

Sorting parameters for TdTom + tumor cells used for seeding secondary allograft tumors.
Supplementary Data Figure S1 from Neuroendocrine Differentiation in Prostate Cancer Requires ASCL1
Authors: Rodarte Kathia E. , Nir Heyman Shaked , Guo Lei , Flores Lydia , Savage Trisha K. , Villarreal Juan , Deng Su , Xu Lin , Shah Rajal B. , Oliver Trudy G. , Johnson Jane E.
Published: November 2024

Genotypes of prostate organoids and resulting allograft tumors.
Data from KHSRP Stabilizes m6A-Modified Transcripts to Activate FAK Signaling and Promote Pancreatic Ductal Adenocarcinoma Progression
Authors: Xu Zilan , Zhou Yifan , Liu Shaoqiu , Zhao Hongzhe , Chen Ziming , Li Rui , Li Mei , Huang Xudong , Deng Shuang , Zeng Lingxing , Zhao Sihan , Zhang Shaoping , He Xiaowei , Liu Ji , Xue Chunling , Bai Ruihong , Zhuang Lisha , Zhou Quanbo , Chen Rufu , Lin Dongxin , Zheng Jian , Zhang Jialiang
Published: November 2024

Abstract
N6-Methyladenosine (m6A) is the most prevalent RNA modification and is associated with various biological processes. Proteins that function as readers and writers of m6A modifications have been shown to play critical roles in human malignancies. Here, we identified KH-type splicing regulatory protein (KHSRP) as an m6A binding protein that contributes to the progression of pancreatic ductal adenocarcinoma (PDAC). High KHSRP levels were detected in PDAC and predicted poor patient survival. KHSRP deficiency suppressed PDAC growth and metastasis in vivo. Mechanistically, KHSRP recognized and stabilized FAK pathway mRNAs, including MET, ITGAV, and ITGB1, in an m6A-dependent manner, which led to activation of downstream FAK signaling that promoted PDAC progression. Targeting KHSRP with a PROTAC showed promising tumor suppressive effects in mouse models, leading to prolonged survival. Together, these findings indicate that KHSRP mediates FAK pathway activation in an m6A-dependent manner to support PDAC growth and metastasis, highlighting the potential of KHSRP as a therapeutic target in pancreatic cancer.

Significance: KHSRP is a m6A-binding protein that stabilizes expression of FAK pathway mRNAs and that can be targeted to suppress FAK signaling and curb pancreatic ductal adenocarcinoma progression.
Data from LX1 Dual Targets AR Variants and AKR1C3 in Advanced Prostate Cancer Therapy
Authors: Ning Shu , Armstrong Cameron M. , Xing Enming , Leslie Amy R. , Gao Richard Y. , Sharifi Masuda , Schaaf Zachary A. , Lou Wei , Han Xiangrui , Xu Desiree H. , Yang Rui , Cheng Jeffrey , Mohammed Shabber , Mitsiades Nicholas , Liu Chengfei , Lombard Alan P. , Wu Chun-Yi , Cheng Xiaolin , Li Pui-Kai , Gao Allen C.
Published: November 2024

Abstract
The development of resistance to current standard-of-care treatments, such as androgen receptor (AR) targeting therapies, remains a major challenge in the management of advanced prostate cancer. There is an urgent need for new therapeutic strategies targeting key resistant drivers, such as AR variants like AR-V7, and steroidogenic enzymes, such as aldo–keto reductase 1C3 (AKR1C3), to overcome drug resistance and improve outcomes for patients with advanced prostate cancer. Here, we have designed, synthesized, and characterized a novel class of LX compounds targeting both the AR/AR variants and AKR1C3 pathways. Molecular docking and in vitro studies demonstrated that LX compounds bind to the AKR1C3 active sites and inhibit AKR1C3 enzymatic activity. LX compounds were also shown to reduce AR/AR-V7 expression and to inhibit their target gene signaling. LX1 inhibited the conversion of androstenedione into testosterone in tumor-based ex vivo enzyme assays. In addition, LX1 inhibited the growth of cells resistant to antiandrogens including enzalutamide (Enza), abiraterone, apalutamide, and darolutamide in vitro. A synergistic effect was observed when LX1 was combined with antiandrogens and taxanes, indicating the potential for this combination in treating resistant prostate cancer. Treatment with LX1 significantly decreased tumor volume, serum PSA levels, as well as reduced intratumoral testosterone levels, without affecting mouse body weight. Furthermore, LX1 was found to overcome resistance to Enza treatment, and its combination with Enza further suppressed tumor growth in both the CWR22Rv1 xenograft and LuCaP35CR patient-derived xenograft models. Collectively, the dual effect of LX1 in reducing AR signaling and intratumoral testosterone, along with its synergy with standard therapies in resistant models, underscores its potential as a valuable treatment option for advanced prostate cancer.

Significance: LX1 simultaneously targets androgen receptor variants and the steroidogenic enzyme AKR1C3, offering a promising approach to combat drug resistance and enhancing therapeutic efficacy in conjunction with standard treatments for advanced prostate cancer.
Data from Targeting BCL2 with Venetoclax Enhances the Efficacy of the KRASG12D Inhibitor MRTX1133 in Pancreatic Cancer
Authors: Becker Jeffrey H. , Metropulos Anastasia E. , Spaulding Christina , Marinelarena Alejandra M. , Shields Mario A. , Principe Daniel R. , Pham Thao D. , Munshi Hidayatullah G.
Published: November 2024

Abstract
MRTX1133 is currently being evaluated in patients with pancreatic ductal adenocarcinoma (PDAC) tumors harboring a KRASG12D mutation. Combination strategies have the potential to enhance the efficacy of MRTX1133 to further promote cell death and tumor regression. In this study, we demonstrated that MRTX1133 increased the levels of the proapoptotic protein BIM in PDAC cells and conferred sensitivity to the FDA-approved BCL2 inhibitor venetoclax. Combined treatment with MRTX1133 and venetoclax resulted in cell death and growth suppression in 3D cultures. BIM was required for apoptosis induced by the combination treatment. Consistently, BIM was induced in tumors treated with MRTX1133, and venetoclax enhanced the efficacy of MRTX1133 in vivo. Venetoclax could also resensitize MRTX1133-resistant PDAC cells to MRTX1133 in 3D cultures, and tumors established from resistant cells responded to the combination of MRTX1133 and venetoclax. These results provide a rationale for the clinical testing of MRTX1133 and venetoclax in patients with PDAC.

Significance: The combination of MRTX1133 and the FDA-approved drug venetoclax promotes cancer cell death and tumor regression in pancreatic ductal adenocarcinoma, providing rationale for testing venetoclax with KRASG12D inhibitors in patients with pancreatic cancer.
Data from NQO1 Triggers Neutrophil Recruitment and NET Formation to Drive Lung Metastasis of Invasive Breast Cancer
Authors: Wang Xinzhi , Qu Yi , Xu Qianqian , Jiang Zeyu , Wang Hang , Lin Binyan , Cao Zehong , Pan Yuqi , Li Sheng , Hu Yili , Yang Hui , He Li , Chang Hang , Hang Bo , Wen Hongmei , Wu Hao , Mao Jian-Hua
Published: November 2024

Abstract
Metastasis to the lungs is a leading cause of death for patients with breast cancer. Therefore, effective therapies are urgently needed to prevent and treat lung metastasis. In this study, we uncovered a mechanism by which NAD(P)H:quinone oxidoreductase 1 (NQO1) orchestrates lung metastasis. NQO1 stabilized and upregulated peptidyl-prolyl cis-trans isomerase A (PPIA), a chaperone that regulates protein conformation and activity, by preventing its oxidation at a critical cysteine residue C161. PPIA subsequently activated CD147, a membrane protein that facilitates cell invasion. Moreover, NQO1-induced secretion of PPIA modulated the immune landscape of both primary and lung metastatic sites. Secreted PPIA engaged CD147 on neutrophils and triggered the release of neutrophil extracellular traps (NET) and neutrophil elastase, which enhanced tumor progression, invasiveness, and lung colonization. Pharmacological targeting of PPIA effectively inhibited NQO1-mediated breast cancer lung metastasis. These findings reveal a previously unrecognized NQO1-PPIA-CD147-NET axis that drives breast cancer lung metastasis. Inhibiting this axis is a potential therapeutic strategy to limit lung metastasis in patients with breast cancer.

 Significance: NQO1 stabilizes and promotes the secretion of PPIA to activate CD147 in neutrophils and stimulate NET formation, promoting breast cancer lung metastasis and providing therapeutic targets for this fatal condition.
Data from CRISPR Screening of Transcribed Super-Enhancers Identifies Drivers of Triple-Negative Breast Cancer Progression
Authors: Lewis Michael W. , King Caitlin M. , Wisniewska Kamila , Regner Matthew J. , Coffey Alisha , Kelly Michael R. , Mendez-Giraldez Raul , Davis Eric S. , Phanstiel Douglas H. , Franco Hector L.
Published: November 2024

Abstract
Triple-negative breast cancer (TNBC) is the most therapeutically recalcitrant form of breast cancer, which is due in part to the paucity of targeted therapies. A systematic analysis of regulatory elements that extend beyond protein-coding genes could uncover avenues for therapeutic intervention. To this end, we analyzed the regulatory mechanisms of TNBC-specific transcriptional enhancers together with their noncoding enhancer RNA (eRNA) transcripts. The functions of the top 30 eRNA-producing super-enhancers were systematically probed using high-throughput CRISPR-interference assays coupled to RNA sequencing that enabled unbiased detection of target genes genome-wide. Generation of high-resolution Hi-C chromatin interaction maps enabled annotation of the direct target genes for each super-enhancer, which highlighted their proclivity for genes that portend worse clinical outcomes in patients with TNBC. Illustrating the utility of this dataset, deletion of an identified super-enhancer controlling the nearby PODXL gene or specific degradation of its eRNAs led to profound inhibitory effects on target gene expression, cell proliferation, and migration. Furthermore, loss of this super-enhancer suppressed tumor growth and metastasis in TNBC mouse xenograft models. Single-cell RNA sequencing and assay for transposase-accessible chromatin with high-throughput sequencing analyses demonstrated the enhanced activity of this super-enhancer within the malignant cells of TNBC tumor specimens compared with nonmalignant cell types. Collectively, this work examines several fundamental questions about how regulatory information encoded into eRNA-producing super-enhancers drives gene expression networks that underlie the biology of TNBC.

Significance: Integrative analysis of eRNA-producing super-enhancers defines molecular mechanisms controlling global patterns of gene expression that regulate clinical outcomes in breast cancer, highlighting the potential of enhancers as biomarkers and therapeutic targets.
Data from FOXP4 Is a Direct YAP1 Target That Promotes Gastric Cancer Stemness and Drives Metastasis
Authors: Liu Xiaoli , Chen Bonan , Xie Fuda , Wong Kit Yee , Cheung Alvin H.K. , Zhang Jinglin , Wu Qian , Fang Canbin , Hu Jintao , Wang Shouyu , Xu Dazhi , Chen Jianwu , Wang Yuzhi , Wong Chi Chun , Chen Huarong , Wu William K.K. , Yu Jun , Chan Michael W.Y. , Tsang Chi Man , Lo Kwok Wai , Tse Gary M.K. , To Ka-Fai , Kang Wei
Published: November 2024

Abstract
The Hippo–YAP1 pathway is an evolutionally conserved signaling cascade that controls organ size and tissue regeneration. Dysregulation of Hippo–YAP1 signaling promotes initiation and progression of several types of cancer, including gastric cancer. As the Hippo–YAP1 pathway regulates expression of thousands of genes, it is important to establish which target genes contribute to the oncogenic program driven by YAP1 to identify strategies to circumvent it. In this study, we identified a vital role of forkhead box protein 4 (FOXP4) in YAP1-driven gastric carcinogenesis by maintaining stemness and promoting peritoneal metastasis. Loss of FOXP4 impaired gastric cancer spheroid formation and reduced stemness marker expression, whereas FOXP4 upregulation potentiated cancer cell stemness. RNA sequencing analysis revealed SOX12 as a downstream target of FOXP4, and functional studies established that SOX12 supports stemness in YAP1-induced carcinogenesis. A small-molecule screen identified 42-(2-tetrazolyl) rapamycin as a FOXP4 inhibitor, and targeting FOXP4 suppressed gastric cancer tumor growth and enhanced the efficacy of 5-fluorouracil chemotherapy in vivo. Collectively, these findings revealed that FOXP4 upregulation by YAP1 in gastric cancer regulates stemness and tumorigenesis by upregulating SOX12. Targeting the YAP1–FOXP4–SOX12 axis represents a potential therapeutic strategy for gastric cancer.

Significance: Hippo–YAP1 signaling maintains stemness in gastric cancer by upregulating FOXP4, identifying FOXP4 as a stemness biomarker and therapeutic target that could help improve patient outcomes.
Data from Targeting Catechol-O-Methyltransferase Induces Mitochondrial Dysfunction and Enhances the Efficacy of Radiotherapy in Glioma
Authors: Jiao Meng , Pirozzi Christopher J. , Yu Chen , Bao Xuhui , Hu Mengjie , Pan Dong , Littleton Sejiro , Reynolds Nathan , Saban Daniel R. , Li Fang , Li Chuan-Yuan
Published: November 2024

Abstract
Radiotherapy (RT) is commonly used to try to eliminate any remaining tumor cells following surgical resection of glioma. However, tumor recurrence is prevalent, highlighting the unmet medical need to develop therapeutic strategies to enhance the efficacy of RT in glioma. Focusing on the radiosensitizing potential of the currently approved drugs known to cross the blood-brain barrier can facilitate rapid clinical translation. Here, we assessed the role of catechol-O-methyltransferase (COMT), a key enzyme to degrade catecholamines and a drug target for Parkinson’s disease, in glioma treatment. Analysis of The Cancer Genome Atlas data showed significantly higher COMT expression levels in both low-grade glioma and glioblastoma compared to normal brain tissues. Inhibition of COMT by genetic knockout or FDA-approved COMT inhibitors significantly sensitized glioma cells to RT in vitro and in vivo. Mechanistically, COMT inhibition in glioma cells led to mitochondria dysfunction and increased mitochondrial RNA release into the cytoplasm, activating the cellular antiviral double-stranded RNA sensing pathway and type I interferon (IFN) response. Elevated type I IFNs stimulated the phagocytic capacity of microglial cells, enhancing RT efficacy. Given the long-established safety record of the COMT inhibitors, these findings provide a solid rationale to evaluate them in combination with RT in patients with glioma.

Significance: Inhibition of catechol-O-methyltransferase, a well-established drug target in Parkinson’s disease, interferes with mitochondrial electron transport and induces mitochondrial double-stranded RNA leakage, activating type I interferon signaling and sensitizing glioma to radiotherapy.
Supplementary Figure S4 from Durvalumab ± Tremelimumab + Platinum-Etoposide in Extensive-Stage Small Cell Lung Cancer (CASPIAN): Outcomes by PD-L1 Expression and Tissue Tumor Mutational Burden
Authors: Paz-Ares Luis , Garassino Marina Chiara , Chen Yuanbin , Reinmuth Niels , Hotta Katsuyuki , Poltoratskiy Artem , Trukhin Dmytro , Hochmair Maximilian J. , Özgüroğlu Mustafa , Ji Jun Ho , Statsenko Galina , Conev Nikolay , Bondarenko Igor , Havel Libor , Losonczy György , Xie Mingchao , Lai Zhongwu , Godin-Heymann Nadia , Mann Helen , Jiang Haiyi , Shrestha Yashaswi , Goldman Jonathan W.
Published: November 2024

Subgroup analysis of confirmed ORR by PD-L1 TC and IC expression for (A) durvalumab plus tremelimumab plus EP versus EP and (B) durvalumab plus EP versus EP. In each panel, the shaded band shows the confidence interval for the ITT population; circle sizes are proportional to the number of responses. Groups are not plotted when there are ≤5 responses across both arms.
Supplementary Figure 3 from Circulating Tumor DNA Analysis Detects FGFR2 Amplification and Concurrent Genomic Alterations Associated with FGFR Inhibitor Efficacy in Advanced Gastric Cancer
Authors: Jogo Tomoko , Nakamura Yoshiaki , Shitara Kohei , Bando Hideaki , Yasui Hisateru , Esaki Taito , Terazawa Tetsuji , Satoh Taroh , Shinozaki Eiji , Nishina Tomohiro , Sunakawa Yu , Komatsu Yoshito , Hara Hiroki , Oki Eiji , Matsuhashi Nobuhisa , Ohta Takashi , Kato Takeshi , Ohtsubo Koushiro , Kawakami Takeshi , Okano Naohiro , Yamamoto Yoshiyuki , Yamada Takanobu , Tsuji Akihito , Odegaard Justin I. , Taniguchi Hiroya , Doi Toshihiko , Fujii Satoshi , Yoshino Takayuki
Published: November 2024

FGFR Immunohistochemical staining and FISH images in biopsy specimens from the primary tumor of Patient 2
Supplementary Figure 1 from Circulating Tumor DNA Analysis Detects FGFR2 Amplification and Concurrent Genomic Alterations Associated with FGFR Inhibitor Efficacy in Advanced Gastric Cancer
Authors: Jogo Tomoko , Nakamura Yoshiaki , Shitara Kohei , Bando Hideaki , Yasui Hisateru , Esaki Taito , Terazawa Tetsuji , Satoh Taroh , Shinozaki Eiji , Nishina Tomohiro , Sunakawa Yu , Komatsu Yoshito , Hara Hiroki , Oki Eiji , Matsuhashi Nobuhisa , Ohta Takashi , Kato Takeshi , Ohtsubo Koushiro , Kawakami Takeshi , Okano Naohiro , Yamamoto Yoshiyuki , Yamada Takanobu , Tsuji Akihito , Odegaard Justin I. , Taniguchi Hiroya , Doi Toshihiko , Fujii Satoshi , Yoshino Takayuki
Published: November 2024

OS based on the Kaplan-Meier method for patients with FGFR2 amplification detected in tissue+ctDNA+ or tissue-ctDNA+ versus in tissue-ctDNA-
Supplemental File 1 from Improving Risk Stratification for Pediatric Patients with Rhabdomyosarcoma by Molecular Detection of Disseminated Disease
Authors: Lak Nathalie S.M. , Voormanns Timon L. , Zappeij-Kannegieter Lily , van Zogchel Lieke M.J. , Fiocco Marta , van Noesel Max M. , Merks Johannes H.M. , van der Schoot C. Ellen , Tytgat Godelieve A.M. , Stutterheim Janine
Published: November 2024

Sanger Sequencing
Supplementary Table 2 from TOP2B Enzymatic Activity on Promoters and Introns Modulates Multiple Oncogenes in Human Gliomas
Authors: Gonzalez-Buendia Edgar , Zhao Junfei , Wang Lu , Mukherjee Subhas , Zhang Daniel , Arrieta Víctor A. , Feldstein Eric , Kane J. Robert , Kang Seong Jae , Lee-Chang Catalina , Mahajan Aayushi , Chen Li , Realubit Ronald , Karan Charles , Magnuson Lisa , Horbinski Craig , Marshall Stacy A. , Sarkaria Jann N. , Mohyeldin Ahmed , Nakano Ichiro , Bansal Mukesh , James Charles D. , Brat Daniel J. , Ahmed Atique , Canoll Peter , Rabadan Raul , Shilatifard Ali , Sonabend Adam M.
Published: November 2024

Detailed quality metrics report with the Library complexity and PCR Bottleneck Coefficient (PBC)
Supplementary Figure 3 from Kinobead Profiling Reveals Reprogramming of BCR Signaling in Response to Therapy within Primary CLL Cells
Authors: Linley Adam J. , Karydis Laura I. , Mondru Anil K. , D'Avola Annalisa , Al Shmrany Humood , Cicconi Silvia , Griffin Rebecca , Forconi Francesco , Pettitt Andrew R. , Kalakonda Nagesh , Rawstron Andrew C. , Hillmen Peter , Steele Andrew J. , MacEwan David J. , Packham Graham , Prior Ian A. , Slupsky Joseph R.
Published: November 2024

Supplementary Figure 3: A; Correlation of kinase mRNA expression determined by Nanostring between treatment naïve (TN) and previously treated (PT) patients. B; Flow cytometric analysis of inhibitory coreceptors and C; immunoblot analysis of phosphatases in three samples from untreated (UT) patients and three samples from previously treated (PT) patients. In B, graph shows results for individual samples and mean ({plus minus}error). In C, GAPDH was analyzed as an additional loading control.
Supplementary Dataset 3 from Kinobead Profiling Reveals Reprogramming of BCR Signaling in Response to Therapy within Primary CLL Cells
Authors: Linley Adam J. , Karydis Laura I. , Mondru Anil K. , D'Avola Annalisa , Al Shmrany Humood , Cicconi Silvia , Griffin Rebecca , Forconi Francesco , Pettitt Andrew R. , Kalakonda Nagesh , Rawstron Andrew C. , Hillmen Peter , Steele Andrew J. , MacEwan David J. , Packham Graham , Prior Ian A. , Slupsky Joseph R.
Published: November 2024

Refined kinome signature ratio data gained from experiments involving primary CLL cells from a cohort of 40 patients.
Figure 4 from Kinobead Profiling Reveals Reprogramming of BCR Signaling in Response to Therapy within Primary CLL Cells
Authors: Linley Adam J. , Karydis Laura I. , Mondru Anil K. , D'Avola Annalisa , Al Shmrany Humood , Cicconi Silvia , Griffin Rebecca , Forconi Francesco , Pettitt Andrew R. , Kalakonda Nagesh , Rawstron Andrew C. , Hillmen Peter , Steele Andrew J. , MacEwan David J. , Packham Graham , Prior Ian A. , Slupsky Joseph R.
Published: November 2024

Alterations to signaling pathways induced by therapy can be detected using kinobead-MS. A, Immunoblotting, comparing activation of BCR signaling mediators in control and sIgM-stimulated cells between representative treatment-naïve (TN) and previously treated (PT) patients. B, Heatmap showing relative changes to kinome capture between signaler patients stratified according to receipt of chemoimmunotherapy. C, Comparison of changes to KEGG pathways associated with our kinome signature between the TN and PT patients used to prepare part B. D, Heatmap comparing sIgM activation kinome fingerprints for ARCTIC/ADMIRE trial patients (n = 10) using their baseline (pre-therapy) sample and their disease progression (DP) sample. E, Graph comparing changes in KEGG pathways between BL and DP patients used to prepare part D.
Table S2 from Prognostic Utility of Breast Cancer Index to Stratify Distant Recurrence Risk in Invasive Lobular Carcinoma
Authors: Nunes Raquel , Sella Tal , Treuner Kai , Atkinson Jennifer M. , Wong Jenna , Zhang Yi , Exman Pedro , Dabbs David , Richardson Andrea L. , Schnabel Catherine A. , Sgroi Dennis C. , Oesterreich Steffi , Cimino-Mathews Ashley , Metzger Otto
Published: November 2024

Number of overall 10-year, early (0-5 years), and late (5-10 years) distant recurrences (DR) by prespecified BCI risk groups for patients with N0 tumors, N+ tumors, and the overall cohort (N0 and N+).
Figure S6 from Prognostic Utility of Breast Cancer Index to Stratify Distant Recurrence Risk in Invasive Lobular Carcinoma
Authors: Nunes Raquel , Sella Tal , Treuner Kai , Atkinson Jennifer M. , Wong Jenna , Zhang Yi , Exman Pedro , Dabbs David , Richardson Andrea L. , Schnabel Catherine A. , Sgroi Dennis C. , Oesterreich Steffi , Cimino-Mathews Ashley , Metzger Otto
Published: November 2024

Prognostic performance of BCI (gene expression only) and BCIN+ (gene expression plus tumor size and grade) for overall 10-year, early (0-5 years), and late (5-10 years) distant recurrence rate in patients with (A) N0 and (B) N+ tumors, respectively.
Figure S5 from Prognostic Utility of Breast Cancer Index to Stratify Distant Recurrence Risk in Invasive Lobular Carcinoma
Authors: Nunes Raquel , Sella Tal , Treuner Kai , Atkinson Jennifer M. , Wong Jenna , Zhang Yi , Exman Pedro , Dabbs David , Richardson Andrea L. , Schnabel Catherine A. , Sgroi Dennis C. , Oesterreich Steffi , Cimino-Mathews Ashley , Metzger Otto
Published: November 2024

Patient distribution of BCI predictive [BCI (H/I)-Low vs. -High] and BCI prognostic groups (BCI Prognostic Low/Intermediate vs. High).
Figure S3 from Prognostic Utility of Breast Cancer Index to Stratify Distant Recurrence Risk in Invasive Lobular Carcinoma
Authors: Nunes Raquel , Sella Tal , Treuner Kai , Atkinson Jennifer M. , Wong Jenna , Zhang Yi , Exman Pedro , Dabbs David , Richardson Andrea L. , Schnabel Catherine A. , Sgroi Dennis C. , Oesterreich Steffi , Cimino-Mathews Ashley , Metzger Otto
Published: November 2024

Case flow diagram of ILC cohort.
Figure S1 from Prognostic Utility of Breast Cancer Index to Stratify Distant Recurrence Risk in Invasive Lobular Carcinoma
Authors: Nunes Raquel , Sella Tal , Treuner Kai , Atkinson Jennifer M. , Wong Jenna , Zhang Yi , Exman Pedro , Dabbs David , Richardson Andrea L. , Schnabel Catherine A. , Sgroi Dennis C. , Oesterreich Steffi , Cimino-Mathews Ashley , Metzger Otto
Published: November 2024

Flow diagram of pilot study comparing manual macro-dissection with laser capture microdissection.
Supplementary Tables from A Phase I Study of LSZ102, an Oral Selective Estrogen Receptor Degrader, with or without Ribociclib or Alpelisib, in Patients with Estrogen Receptor–Positive Breast Cancer
Authors: Jhaveri Komal , Juric Dejan , Yap Yoon-Sim , Cresta Sara , Layman Rachel M. , Duhoux Francois P. , Terret Catherine , Takahashi Shunji , Huober Jens , Kundamal Nicole , Sheng Qing , Balbin Alejandro , Ji Yan , He Wei , Crystal Adam , De Vita Serena , Curigliano Giuseppe
Published: November 2024

The supplementary tables file contains four individual tables detailing: exclusions from the dose-determining set, treatment-related serious AEs, steady-state LSZ102 PK parameters, and a summary of best overall responses by treatment arm.
Supplementary Figure 7 from A Phase I Study of LSZ102, an Oral Selective Estrogen Receptor Degrader, with or without Ribociclib or Alpelisib, in Patients with Estrogen Receptor–Positive Breast Cancer
Authors: Jhaveri Komal , Juric Dejan , Yap Yoon-Sim , Cresta Sara , Layman Rachel M. , Duhoux Francois P. , Terret Catherine , Takahashi Shunji , Huober Jens , Kundamal Nicole , Sheng Qing , Balbin Alejandro , Ji Yan , He Wei , Crystal Adam , De Vita Serena , Curigliano Giuseppe
Published: November 2024

Supplementary figure 7 shows progression-free survival (Kaplan-Meier) by baseline ESR1 and PIK3CA mutation status in both combination treatment arms.
Supplementary Table S1 from Phase I Study of 2- or 3-Week Dosing of Telisotuzumab Vedotin, an Antibody–Drug Conjugate Targeting c-Met, Monotherapy in Patients with Advanced Non–Small Cell Lung Carcinoma
Authors: Camidge D. Ross , Morgensztern Daniel , Heist Rebecca S. , Barve Minal , Vokes Everett , Goldman Jonathan W. , Hong David S. , Bauer Todd M. , Strickler John H. , Angevin Eric , Motwani Monica , Parikh Apurvasena , Sun Zhaowen , Bach Bruce Allen , Wu Jun , Komarnitsky Philip B. , Kelly Karen
Published: November 2024

Supplementary Table S1 shows prior anticancer therapies
Supplementary Figure 4 from A Phase I Study of LSZ102, an Oral Selective Estrogen Receptor Degrader, with or without Ribociclib or Alpelisib, in Patients with Estrogen Receptor–Positive Breast Cancer
Authors: Jhaveri Komal , Juric Dejan , Yap Yoon-Sim , Cresta Sara , Layman Rachel M. , Duhoux Francois P. , Terret Catherine , Takahashi Shunji , Huober Jens , Kundamal Nicole , Sheng Qing , Balbin Alejandro , Ji Yan , He Wei , Crystal Adam , De Vita Serena , Curigliano Giuseppe
Published: November 2024

Supplementary figure 4 shows the baseline tumor mutation status in each arm for those who achieved a defined clinical benefit on treatment versus those who did not.
Supplementary Data from Therapeutic Targeting of Mesothelin with Chimeric Antigen Receptor T Cells in Acute Myeloid Leukemia
Authors: Le Quy , Castro Sommer , Tang Thao , Loeb Anisha M. , Hylkema Tiffany , McKay Cyd Nourigat , Perkins LaKeisha , Srivastava Shivani , Call Lindsey , Smith Jenny , Leonti Amanda , Ries Rhonda , Pardo Laura , Loken Michael R. , Correnti Colin , Fiorenza Salvatore , Turtle Cameron J. , Riddell Stanley , Tarlock Katherine , Meshinchi Soheil
Published: November 2024

Supplemental Table and Figure
Supplement 2 from A Phase I Study of LSZ102, an Oral Selective Estrogen Receptor Degrader, with or without Ribociclib or Alpelisib, in Patients with Estrogen Receptor–Positive Breast Cancer
Authors: Jhaveri Komal , Juric Dejan , Yap Yoon-Sim , Cresta Sara , Layman Rachel M. , Duhoux Francois P. , Terret Catherine , Takahashi Shunji , Huober Jens , Kundamal Nicole , Sheng Qing , Balbin Alejandro , Ji Yan , He Wei , Crystal Adam , De Vita Serena , Curigliano Giuseppe
Published: November 2024

Supplement 2 contains the trial statistical analysis plan.
Supplementary Data from Biomarker Analysis of the Phase III NALA Study of Neratinib + Capecitabine versus Lapatinib + Capecitabine in Patients with Previously Treated Metastatic Breast Cancer
Authors: Saura Cristina , Matito Judit , Oliveira Mafalda , Wildiers Hans , Brufksy Adam M. , Waters Simon H. , Hurvitz Sara A. , Moy Beverly , Kim Sung-Bae , Gradishar William J. , Queiroz Geraldo Silva , Cronemberger Eduardo , Wallweber Gerald J. , Bebchuk Judith , Keyvanjah Kiana , Lalani Alshad S. , Bryce Richard , Vivancos Ana , Eli Lisa D. , Delaloge Suzette
Published: November 2024

Supplementary methods and supplementary tables (Table S1. VHIO-Card amplicon-seq panel v4: regions included; TABLE S2. Patient characteristics according to availability of NGS and HER2 test results; TABLE S3. HER2 scores stratified by hormone receptor status; TABLE S4. HER2 scores stratified by PIK3CA mutation status) and supplementary figures (Figure S1. Biomarker testing flow diagram; Figure S2. Spectrum of mutations detected: (A) PIK3CA; (B) HER2; (C) HER3; (D) AKT1; (E) ESR1; and (F) KRAS.)
Data from Improving Risk Stratification for Pediatric Patients with Rhabdomyosarcoma by Molecular Detection of Disseminated Disease
Authors: Lak Nathalie S.M. , Voormanns Timon L. , Zappeij-Kannegieter Lily , van Zogchel Lieke M.J. , Fiocco Marta , van Noesel Max M. , Merks Johannes H.M. , van der Schoot C. Ellen , Tytgat Godelieve A.M. , Stutterheim Janine
Published: November 2024

AbstractPurpose:
Survival of children with rhabdomyosarcoma that suffer from recurrent or progressive disease is poor. Identifying these patients upfront remains challenging, indicating a need for improvement of risk stratification. Detection of tumor-derived mRNA in bone marrow (BM) and peripheral blood (PB) using reverse-transcriptase qPCR (RT-qPCR) is a more sensitive method to detect disseminated disease. We identified a panel of genes to optimize risk stratification by RT-qPCR.
Experimental Design:
Candidate genes were selected using gene expression data from rhabdomyosarcoma and healthy hematologic tissues, and a multiplexed RT-qPCR was developed. Significance of molecular disease was determined in a cohort of 99 Dutch patients with rhabdomyosarcoma (72 localized and 27 metastasized) treated according to the European pediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 protocol.
Results:
We identified the following 11 rhabdomyosarcoma markers: ZIC1, ACTC1, MEGF10, PDLIM3, SNAI2, CDH11, TMEM47, MYOD1, MYOG, and PAX3/7-FOXO1. RT-qPCR was performed for this 11-marker panel on BM and PB samples from the patient cohort. Five-year event-free survival (EFS) was 35.5% [95% confidence interval (CI), 17.5%–53.5%] for the 33/99 RNA-positive patients, versus 88.0% (95% CI, 78.9%–97.2%) for the 66/99 RNA-negative patients (P < 0.0001). Five-year overall survival (OS) was 54.8% (95% CI, 36.2%–73.4%) and 93.7% (95% CI, 86.6%–100.0%), respectively (P < 0.0001). RNA panel positivity was negatively associated with EFS (Hazard Ratio = 9.52; 95% CI, 3.23–28.02), whereas the RMS2005 risk group stratification was not, in the multivariate Cox regression model.
Conclusions:
This study shows a strong association between PCR-based detection of disseminated disease at diagnosis with clinical outcome in pediatric patients with rhabdomyosarcoma, also compared with conventional risk stratification. This warrants further validation in prospective trials as additional technique for risk stratification.
Data from Kinobead Profiling Reveals Reprogramming of BCR Signaling in Response to Therapy within Primary CLL Cells
Authors: Linley Adam J. , Karydis Laura I. , Mondru Anil K. , D'Avola Annalisa , Al Shmrany Humood , Cicconi Silvia , Griffin Rebecca , Forconi Francesco , Pettitt Andrew R. , Kalakonda Nagesh , Rawstron Andrew C. , Hillmen Peter , Steele Andrew J. , MacEwan David J. , Packham Graham , Prior Ian A. , Slupsky Joseph R.
Published: November 2024

AbstractPurpose:
B-cell receptor (BCR) signaling is critical for the pathogenesis of chronic lymphocytic leukemia (CLL), promoting both malignant cell survival and disease progression. Although vital, understanding of the wider signaling network associated with malignant BCR stimulation is poor. This is relevant with respect to potential changes in response to therapy, particularly involving kinase inhibitors. In the current study, we describe a novel high-resolution approach to investigate BCR signaling in primary CLL cells and track the influence of therapy on signaling response.
Experimental Design:
A kinobead/mass spectrometry–based protocol was used to study BCR signaling in primary CLL cells. Longitudinal analysis of samples donated by clinical trial patients was used to investigate the impact of chemoimmunotherapy and ibrutinib on signaling following surface IgM engagement. Complementary Nanostring and immunoblotting analysis was used to verify our findings.
Results:
Our protocol isolated a unique, patient-specific signature of over 30 kinases from BCR-stimulated CLL cells. This signature was associated with 13 distinct Kyoto Encyclopedia of Genes and Genomes pathways and showed significant change in cells from treatment-naïve patients compared with those from patients who had previously undergone therapy. This change was validated by longitudinal analysis of clinical trials samples where BCR-induced kinome responses in CLL cells altered between baseline and disease progression in patients failing chemoimmunotherapy and between baseline and treatment in patients taking ibrutinib.
Conclusions:
These data comprise the first comprehensive proteomic investigation of the BCR signaling response within CLL cells and reveal unique evidence that these cells undergo adaptive reprogramming of this signaling in response to therapy.