bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Reciprocal Regulation of DUSP9 and DUSP16 Expression by HIF1 Controls ERK and p38 MAP Kinase Activity and Mediates Chemotherapy-Induced Breast Cancer Stem Cell Enrichment
Authors: Lu Haiquan , Tran Linh , Park Youngrok , Chen Ivan , Lan Jie , Xie Yangyiran , Semenza Gregg L.
Published: March 2023

Abstract
Triple-negative breast cancer (TNBC) has a poor prognosis due to its aggressive characteristics and lack of targeted therapies. Cytotoxic chemotherapy may reduce tumor bulk, but leaves residual disease due to the persistence of chemotherapy-resistant breast cancer stem cells (BCSC), which are critical for tumor recurrence and metastasis. Here, we demonstrate that hypoxia-inducible factor (HIF)-1–dependent regulation of mitogen-activated protein kinase (MAPK) signaling pathways contributes to chemotherapy-induced BCSC enrichment. Chemotherapy increased DUSP9 expression and decreased DUSP16 expression in a HIF1–dependent manner, leading to inhibition of ERK and activation of p38 signaling pathways, respectively. Inhibition of ERK caused transcriptional induction of the pluripotency factor Nanog through decreased inactivating phosphorylation of FoxO3, while activation of p38 stabilized Nanog and Klf4 mRNA through increased inactivating phosphorylation of RNA-binding protein ZFP36L1, both of which promoted specification of the BCSC phenotype. Inhibition of HIF1 or p38 signaling blocked chemotherapy-induced pluripotency factor expression and BCSC enrichment. These surprising results delineate a mechanism by which a transcription factor switches cells from ERK to p38 signaling in response to chemotherapy and suggest that therapeutic targeting of HIF1 or the p38 pathway in combination with chemotherapy will block BCSC enrichment and improve outcome in TNBC.

Significance: These findings provide a molecular mechanism that may account for the increased relapse rate of women with TNBC who are treated with cytotoxic chemotherapy and suggest that combining chemotherapy with an inhibitor of HIF1 or p38 activity may increase patient survival. Cancer Res; 78(15); 4191–202. ©2018 AACR.
Data from LPA4-Mediated Vascular Network Formation Increases the Efficacy of Anti–PD-1 Therapy against Brain Tumors
Authors: Eino Daisuke , Tsukada Yohei , Naito Hisamichi , Kanemura Yonehiro , Iba Tomohiro , Wakabayashi Taku , Muramatsu Fumitaka , Kidoya Hiroyasu , Arita Hideyuki , Kagawa Naoki , Fujimoto Yasunori , Takara Kazuhiro , Kishima Haruhiko , Takakura Nobuyuki
Published: March 2023

Abstract
The structure and function of tumor blood vessels profoundly affects the tumor microenvironment. Signals mediated through the lysophosphatidic acid receptor 4 (LPA4) promote vascular network formation to restore normal vascular barrier function in subcutaneous tumors and thus improve drug delivery. However, the characteristics of the vasculature vary by organ and tumor types, and how drug delivery and leukocyte trafficking are affected by modification of vascular function by LPA in different cancers is unclear. Here, we show that LPA4 activation promotes the formation of fine vascular structures in brain tumors. RhoA/ROCK signaling contributed to LPA-induced endothelial cell–cell adhesion, and RhoA/ROCK activity following LPA4 stimulation regulated expression of VCAM-1. This resulted in increased lymphocyte infiltration into the tumor. LPA improved delivery of exogenous IgG into brain tumors and enhanced the anticancer effect of anti–programmed cell death-1 antibody therapy. These results indicate the effects of LPA on vascular structure and function apply not only to chemotherapy but also to immunotherapy.
Significance:
These findings demonstrate that lysophosphatidic acid, a lipid mediator, promotes development of a fine capillary network in brain tumors by inducing tightening of endothelial cell-to-cell adhesion, facilitating improved drug delivery, and lymphocyte penetration.
Data from TCIApathfinder: An R Client for the Cancer Imaging Archive REST API
Authors: Russell Pamela , Fountain Kelly , Wolverton Dulcy , Ghosh Debashis
Published: March 2023

Abstract
The Cancer Imaging Archive (TCIA) hosts publicly available deidentified medical images of cancer from over 25 body sites and over 30,000 patients. Over 400 published studies have utilized freely available TCIA images. Images and metadata are available for download through a web interface or a REST API. Here, we present TCIApathfinder, an R client for the TCIA REST API. TCIApathfinder wraps API access in user-friendly R functions that can be called interactively within an R session or easily incorporated into scripts. Functions are provided to explore the contents of the large database and to download image files. TCIApathfinder provides easy access to TCIA resources in the highly popular R programming environment. TCIApathfinder is freely available under the MIT license as a package on CRAN (https://cran.r-project.org/web/packages/TCIApathfinder/index.html) and from https://github.com/pamelarussell/TCIApathfinder.

Significance: These findings present a new tool, TCIApathfinder, the first client for The Cancer Imaging Archive (TCIA) for use in the highly popular R computing environment, that will dramatically lower the barrier of access to the valuable tools in TCIA. Cancer Res; 78(15); 4424–6. ©2018 AACR.
Data from Nuclear Receptor LRH-1 Functions to Promote Castration-Resistant Growth of Prostate Cancer via Its Promotion of Intratumoral Androgen Biosynthesis
Authors: Xiao Lijia , Wang Yuliang , Xu Kexin , Hu Hao , Xu Zhenyu , Wu Dinglan , Wang Zhu , You Wenxing , Ng Chi-Fai , Yu Shan , Chan Franky Leung
Published: March 2023

Abstract
Targeting of steroidogenic enzymes (e.g., abiraterone acetate targeting CYP17A1) has been developed as a novel therapeutic strategy against metastatic castration-resistant prostate cancer (CRPC). However, resistance to steroidal inhibitors inevitably develops in patients, the mechanisms of which remain largely unknown. Liver receptor homolog-1 (LRH-1, NR5A2) is a nuclear receptor, originally characterized as an important regulator of some liver-specific metabolic genes. Here, we report that LRH-1, which exhibited an increased expression pattern in high-grade prostate cancer and CRPC xenograft models, functions to promote de novo androgen biosynthesis via its direct transactivation of several key steroidogenic enzyme genes, elevating intratumoral androgen levels and reactivating AR signaling in CRPC xenografts as well as abiraterone-treated CRPC tumors. Pharmacologic inhibition of LRH-1 activity attenuated LRH-1–mediated androgen deprivation and anti-androgen resistance of prostate cancer cells. Our findings not only demonstrate the significant role of LRH-1 in the promotion of intratumoral androgen biosynthesis in CRPC via its direct transcriptional control of steroidogenesis, but also suggest targeting LRH-1 could be a potential therapeutic strategy for CRPC management.

Significance: These findings not only demonstrate the significant role of the nuclear receptor LRH-1 in the promotion of intratumoral androgen biosynthesis in CRPC via its direct transcriptional control of steroidogenesis, but also suggest targeting LRH-1 could be a potential therapeutic strategy for CRPC management. Cancer Res; 78(9); 2205–18. ©2018 AACR.
Data from Landscape of Germline and Somatic Mitochondrial DNA Mutations in Pediatric Malignancies
Authors: Triska Petr , Kaneva Kristiyana , Merkurjev Daria , Sohail Noor , Falk Marni J. , Triche Timothy J. , Biegel Jaclyn A. , Gai Xiaowu
Published: March 2023

Abstract
Little is known about the spectrum of mitochondrial DNA (mtDNA) mutations across pediatric malignancies. In this study, we analyzed matched tumor and normal whole genome sequencing data from 616 pediatric patients with hematopoietic malignancies, solid tumors, and brain tumors. We identified 391 mtDNA mutations in 284 tumors including 45 loss-of-function mutations, which clustered at four statistically significant hotspots in MT-COX3, MT-ND4, and MT-ND5, and at a mutation hotspot in MT-tRNA-MET. A skewed ratio (4.83) of nonsynonymous versus synonymous (dN/dS) mtDNA mutations with high statistical significance was identified on the basis of Monte Carlo simulations in the tumors. In comparison, opposite ratios of 0.44 and 0.93 were observed in 616 matched normal tissues and in 249 blood samples from children without cancer, respectively. mtDNA mutations varied by cancer type and mtDNA haplogroup. Collectively, these results suggest that deleterious mtDNA mutations play a role in the development and progression of pediatric cancers.
Significance:
This pan-cancer mtDNA study establishes the landscape of germline and tumor mtDNA mutations and identifies hotspots of tumor mtDNA mutations to pinpoint key mitochondrial functions in pediatric malignancies.
Data from Exosomes from Nischarin-Expressing Cells Reduce Breast Cancer Cell Motility and Tumor Growth
Authors: Maziveyi Mazvita , Dong Shengli , Baranwal Somesh , Mehrnezhad Ali , Rathinam Rajamani , Huckaba Thomas M. , Mercante Donald E. , Park Kidong , Alahari Suresh K.
Published: March 2023

Abstract
Exosomes are small extracellular microvesicles that are secreted by cells when intracellular multivesicular bodies fuse with the plasma membrane. We have previously demonstrated that Nischarin inhibits focal adhesion formation, cell migration, and invasion, leading to reduced activation of focal adhesion kinase. In this study, we propose that the tumor suppressor Nischarin regulates the release of exosomes. When cocultured on exosomes from Nischarin-positive cells, breast cancer cells exhibited reduced survival, migration, adhesion, and spreading. The same cocultures formed xenograft tumors of significantly reduced volume following injection into mice. Exosomes secreted by Nischarin-expressing tumors inhibited tumor growth. Expression of only one allele of Nischarin increased secretion of exosomes, and Rab14 activity modulated exosome secretions and cell growth. Taken together, this study reveals a novel role for Nischarin in preventing cancer cell motility, which contributes to our understanding of exosome biology.
Significance:
Regulation of Nischarin-mediated exosome secretion by Rab14 seems to play an important role in controlling tumor growth and migration.

See related commentary by McAndrews and Kalluri, p. 2099
Data from Absence of HIF1A Leads to Glycogen Accumulation and an Inflammatory Response That Enables Pancreatic Tumor Growth
Authors: Maruggi Marco , Layng Fabiana Izidro , Lemos Robert , Garcia Guillermina , James Brian P. , Sevilla Monica , Soldevilla Ferran , Baaten Bas J. , de Jong Petrus R. , Koh Mei Yee , Powis Garth
Published: March 2023

Abstract
Cancer cells respond to hypoxia by upregulating the hypoxia-inducible factor 1α (HIF1A) transcription factor, which drives survival mechanisms that include metabolic adaptation and induction of angiogenesis by VEGF. Pancreatic tumors are poorly vascularized and severely hypoxic. To study the angiogenic role of HIF1A, and specifically probe whether tumors are able to use alternative pathways in its absence, we created a xenograft mouse tumor model of pancreatic cancer lacking HIF1A. After an initial delay of about 30 days, the HIF1A-deficient tumors grew as rapidly as the wild-type tumors and had similar vascularization. These changes were maintained in subsequent passages of tumor xenografts in vivo and in cell lines ex vivo. There were many cancer cells with a "clear-cell" phenotype in the HIF1A-deficient tumors; this was the result of accumulation of glycogen. Single-cell RNA sequencing (scRNA-seq) of the tumors identified hypoxic cancer cells with inhibited glycogen breakdown, which promoted glycogen accumulation and the secretion of inflammatory cytokines, including interleukins 1β (IL1B) and 8 (IL8). scRNA-seq of the mouse tumor stroma showed enrichment of two subsets of myeloid dendritic cells (cDC), cDC1 and cDC2, that secreted proangiogenic cytokines. These results suggest that glycogen accumulation associated with a clear-cell phenotype in hypoxic cancer cells lacking HIF1A can initiate an alternate pathway of cytokine and DC-driven angiogenesis. Inhibiting glycogen accumulation may provide a treatment for cancers with the clear-cell phenotype.
Significance:
These findings establish a novel mechanism by which tumors support angiogenesis in an HIF1α-independent manner.
Data from Predictive Signatures Inform the Effective Repurposing of Decitabine to Treat KRAS–Dependent Pancreatic Ductal Adenocarcinoma
Authors: Mottini Carla , Tomihara Hideo , Carrella Diego , Lamolinara Alessia , Iezzi Manuela , Huang Justin K. , Amoreo Carla A. , Buglioni Simonetta , Manni Isabella , Robinson Frederick S. , Minelli Rosalba , Kang Ya'an , Fleming Jason B. , Kim Michael P. , Bristow Christopher A. , Trisciuoglio Daniela , Iuliano Antonella , Del Bufalo Donatella , Di Bernardo Diego , Melisi Davide , Draetta Giulio F. , Ciliberto Gennaro , Carugo Alessandro , Cardone Luca
Published: March 2023

Abstract
Mutated KRAS protein is a pivotal tumor driver in pancreatic cancer. However, despite comprehensive efforts, effective therapeutics that can target oncogenic KRAS are still under investigation or awaiting clinical approval. Using a specific KRAS–dependent gene signature, we implemented a computer-assisted inspection of a drug–gene network to in silico repurpose drugs that work like inhibitors of oncogenic KRAS. We identified and validated decitabine, an FDA-approved drug, as a potent inhibitor of growth in pancreatic cancer cells and patient-derived xenograft models that showed KRAS dependency. Mechanistically, decitabine efficacy was linked to KRAS–driven dependency on nucleotide metabolism and its ability to specifically impair pyrimidine biosynthesis in KRAS–dependent tumors cells. These findings also showed that gene signatures related to KRAS dependency might be prospectively used to inform on decitabine sensitivity in a selected subset of patients with KRAS–mutated pancreatic cancer. Overall, the repurposing of decitabine emerged as an intriguing option for treating pancreatic tumors that are addicted to mutant KRAS, thus offering opportunities for improving the arsenal of therapeutics for this extremely deadly disease.
Significance:
Decitabine is a promising drug for cancer cells dependent on RAS signaling.
Data from STAT3-Mediated Astrocyte Reactivity Associated with Brain Metastasis Contributes to Neurovascular Dysfunction
Authors: Sarmiento Soto Manuel , Larkin James R. , Martin Chris , Khrapitchev Alexandre A. , Maczka Melissa , Economopoulos Vasiliki , Scott Helen , Escartin Carole , Bonvento Gilles , Serres Sébastien , Sibson Nicola R.
Published: March 2023

Abstract
Astrocytes are thought to play a pivotal role in coupling neural activity and cerebral blood flow. However, it has been shown that astrocytes undergo morphologic changes in response to brain metastasis, switching to a reactive phenotype, which has the potential to significantly compromise cerebrovascular function and contribute to the neurological sequelae associated with brain metastasis. Given that STAT3 is a key regulator of astrocyte reactivity, we aimed here to determine the impact of STAT3-mediated astrocyte reactivity on neurovascular function in brain metastasis. Rat models of brain metastasis and ciliary neurotrophic factor were used to induce astrocyte reactivity. Multimodal imaging, electrophysiology, and IHC were performed to determine the relationship between reactive astrocytes and changes in the cerebrovascular response to electrical and physiological stimuli. Subsequently, the STAT3 pathway in astrocytes was inhibited with WP1066 to determine the role of STAT3-mediated astrocyte reactivity, specifically, in brain metastasis. Astrocyte reactivity associated with brain metastases impaired cerebrovascular responses to stimuli at both the cellular and functional level and disrupted astrocyte–endothelial interactions in both animal models and human brain metastasis samples. Inhibition of STAT3-mediated astrocyte reactivity in rats with brain metastases restored cerebrovascular function, as shown by in vivo imaging, and limited cerebrovascular changes associated with tumor growth. Together these findings suggest that inhibiting STAT3-mediated astrocyte reactivity may confer significant improvements in neurological outcome for patients with brain metastases and could potentially be tested in other brain tumors.
Significance:
These findings demonstrate that selectively targeting STAT3-mediated astrocyte reactivity ameliorates the cerebrovascular dysfunction associated with brain metastasis, providing a potential therapeutic avenue for improved patient outcome.
Data from Visualization of Activated T Cells by OX40-ImmunoPET as a Strategy for Diagnosis of Acute Graft-versus-Host Disease
Authors: Alam Israt S. , Simonetta Federico , Scheller Lukas , Mayer Aaron T. , Murty Surya , Vermesh Ophir , Nobashi Tomomi W. , Lohmeyer Juliane K. , Hirai Toshihito , Baker Jeanette , Lau Kenneth H. , Negrin Robert , Gambhir Sanjiv S.
Published: March 2023

Abstract
Graft-versus-host disease (GvHD) is a major complication of allogeneic hematopoietic cell transplantation (HCT), mediated primarily by donor T cells that become activated and attack host tissues. Noninvasive strategies detecting T-cell activation would allow for early diagnosis and possibly more effective management of HCT recipients. PET imaging is a sensitive and clinically relevant modality ideal for GvHD diagnosis, and there is a strong rationale for the use of PET tracers that can monitor T-cell activation and expansion with high specificity. The TNF receptor superfamily member OX40 (CD134) is a cell surface marker that is highly specific for activated T cells, is upregulated during GvHD, and mediates disease pathogenesis. We recently reported the development of an antibody-based activated T-cell imaging agent targeting OX40. In the present study, we visualize the dynamics of OX40 expression in an MHC-mismatch mouse model of acute GvHD using OX40-immunoPET. This approach enabled visualization of T-cell activation at early stages of disease, prior to overt clinical symptoms with high sensitivity and specificity. This study highlights the potential utility of the OX40 PET imaging as a new strategy for GvHD diagnosis and therapy monitoring.
Significance:
OX40-immunoPET imaging is a promising noninvasive strategy for early detection of GvHD, capable of detecting signs of GvHD pathology even prior to the development of overt clinical symptoms.
Data from Time-Dependent Effects of Oral Contraceptive Use on Breast, Ovarian, and Endometrial Cancers
Authors: Karlsson Torgny , Johansson Therese , Höglund Julia , Ek Weronica E. , Johansson Åsa
Published: March 2023

Abstract
Oral contraceptive use has been suggested to influence the risk of breast, ovarian, and endometrial cancer. The purpose of this study is to clarify the time-dependent effects between long-term oral contraceptive use and cancer risk. We performed an observational study in 256,661 women from UK Biobank, born between 1939 and 1970. Information on cancer diagnoses were collected from self-reported data and from national registers until March 2019. Cumulative risk of cancer over the timespan of the study, as measured by the OR, and instantaneous risk, as measured by the HR, were assessed using Logistic and Cox regression analyses, respectively. The odds were lower among ever users, compared with never users, for ovarian cancer [OR = 0.72; 95% confidence interval (CI), 0.65–0.81] and endometrial cancer (OR = 0.68; 95% CI, 0.62–0.75), an association that was stronger with longer use (P < 0.001). Increased odds were seen for breast cancer in women when limiting the follow-up to 55 years of age (OR = 1.10; 95% CI, 1.03–1.17), but not for the full timespan. We only found a higher HR for breast cancer in former users immediately (≤2 years) after discontinued oral contraceptive use (HR = 1.55; 95% CI, 1.06–2.28), whereas the protective association for ovarian and endometrial cancer remained significant up to 35 years after last use of oral contraceptives. Given the body of evidence presented in our study, we argue that oral contraceptives can dramatically reduce women's risk of ovarian and endometrial cancer, whereas their effect on lifetime risk of breast cancer is limited.
Significance:
These results enable women and physicians to make more informed decisions considering oral contraceptive use, thus constituting an important step toward personalized medicine.
Data from BRD9 Is a Critical Regulator of Androgen Receptor Signaling and Prostate Cancer Progression
Authors: Alpsoy Aktan , Utturkar Sagar M. , Carter Benjamin C. , Dhiman Alisha , Torregrosa-Allen Sandra E. , Currie Melanie P. , Elzey Bennett D. , Dykhuizen Emily C.
Published: March 2023

Abstract
Switch/sucrose-nonfermentable (SWI/SNF) chromatin-remodeling complexes are critical regulators of chromatin dynamics during transcription, DNA replication, and DNA repair. A recently identified SWI/SNF subcomplex termed GLTSCR1/1L-BAF (GBAF; or “noncanonical BAF”, ncBAF) uniquely contains bromodomain-containing protein BRD9 and glioma tumor suppressor candidate region 1 (GLTSCR1) or its paralog GLTSCR1-like (GLTSCR1L). Recent studies have identified a unique dependency on GBAF (ncBAF) complexes in synovial sarcoma and malignant rhabdoid tumors, both of which possess aberrations in canonical BAF (cBAF) and Polybromo-BAF (PBAF) complexes. Dependencies on GBAF in malignancies without SWI/SNF aberrations, however, are less defined. Here, we show that GBAF, particularly its BRD9 subunit, is required for the viability of prostate cancer cell lines in vitro and for optimal xenograft tumor growth in vivo. BRD9 interacts with androgen receptor (AR) and CCCTC-binding factor (CTCF), and modulates AR-dependent gene expression. The GBAF complex exhibits overlapping genome localization and transcriptional targets as bromodomain and extraterminal domain–containing (BET) proteins, which are established AR coregulators. Our results demonstrate that GBAF is critical for coordinating SWI/SNF–BET cooperation and uncover a new druggable target for AR-positive prostate cancers, including those resistant to androgen deprivation or antiandrogen therapies.
Significance:
Advanced prostate cancers resistant to androgen receptor antagonists are still susceptible to nontoxic BRD9 inhibitors, making them a promising alternative for halting AR signaling in progressed disease.
Data from The Mechanisms of Action of Tumor Treating Fields
Authors: Moser Justin C. , Salvador Ellaine , Deniz Karina , Swanson Kenneth , Tuszynski Jack , Carlson Kristen W. , Karanam Narasimha Kumar , Patel Chirag B. , Story Michael , Lou Emil , Hagemann Carsten
Published: March 2023

Abstract
Tumor treating fields (TTFields), a new modality of cancer treatment, are electric fields transmitted transdermally to tumors. The FDA has approved TTFields for the treatment of glioblastoma multiforme and mesothelioma, and they are currently under study in many other cancer types. While antimitotic effects were the first recognized biological anticancer activity of TTFields, data have shown that tumor treating fields achieve their anticancer effects through multiple mechanisms of action. TTFields therefore have the ability to be useful for many cancer types in combination with many different treatment modalities. Here, we review the current understanding of TTFields and their mechanisms of action.
Data from Deregulation of SPOP in Cancer
Authors: Zhang Hui , Jin Xiaofeng , Huang Haojie
Published: March 2023

Abstract
Speckle-type POZ protein (SPOP) is a substrate-binding adaptor of the CULLIN3/RING-box1 E3 ubiquitin ligase complex. SPOP is frequently mutated in prostate and endometrial cancers, whereas it is overexpressed in renal cell carcinoma (RCC). SPOP can mediate both degradable and nondegradable polyubiquitination of a number of substrates with diverse biological functions such as androgen receptor (AR), SRC-3, TRIM24, BRD4, PD-L1, 53BP1, GLP/G9a, c-Myc, SENP7, among others. Cancer-associated SPOP mutants often impair SPOP binding and polyubiquitination of its substrates to influence various cancer-relevant pathways, which include androgen/AR signaling, DNA repair and methylation, cellular stress surveillance, cancer metabolism, and immunity. Although SPOP is recognized as a tumor suppressor in prostate and endometrial cancers, it acts like an oncoprotein in RCC. This review provides an overview of the recent progress in understanding of the upstream regulators of SPOP and its downstream targets, highlights the significant impact of SPOP mutations and overexpression on cancer pathogenesis, and discusses the potential of targeting SPOP for cancer treatment.
Data from METTL1-Mediated m7G tRNA Modification Promotes Lenvatinib Resistance in Hepatocellular Carcinoma
Authors: Huang Manling , Long Jianting , Yao Zhijia , Zhao Yi , Zhao Yutong , Liao Junbin , Lei Kai , Xiao Han , Dai Zihao , Peng Sui , Lin Shuibin , Xu Lixia , Kuang Ming
Published: March 2023

Abstract
The tyrosine kinase inhibitor lenvatinib is a first-line drug for treating patients with advanced hepatocellular carcinoma (HCC). However, its efficacy is severely hampered by drug resistance. Insights into the molecular mechanisms underlying lenvatinib resistance could provide new strategies to improve and prolong responses. Here, we performed unbiased proteomic screening of parental and lenvatinib-resistant HCC cells and discovered that methyltransferase-like protein-1 (METTL1) and WD repeat domain 4 protein (WDR4), the two key components of the tRNA N7-methylguanosine (m7G) methyltransferase complex, were dramatically upregulated in lenvatinib-resistant cells. METTL1 knockdown overrode resistance by impairing the proliferation capacity of HCC cells and promoting apoptosis under lenvatinib treatment. In addition, overexpression of wild-type METTL1 but not its catalytic dead mutant induced lenvatinib resistance. Animal experiments including hydrodynamic injection, subcutaneous implantation, and orthotopic xenograft mouse models further demonstrated the critical function of METTL1/WDR4-mediated m7G tRNA modification in promoting lenvatinib resistance in vivo. Mechanistically, METTL1 promoted translation of EGFR pathway genes to trigger drug resistance. This work reveals the important role of METTL1-mediated m7G tRNA modification in promoting lenvatinib resistance and provides a promising prediction marker and intervention target for resistance.
Significance:
Upregulation of tRNA m7G methyltransferase complex components METTL1 and WDR4 promotes lenvatinib resistance in HCC and confers a sensitivity to METTL1 targeting, providing a promising strategy to override resistance.
Data from Sequential Targeting of Retinoblastoma and DNA Synthesis Pathways Is a Therapeutic Strategy for Sarcomas That Can Be Monitored in Real Time
Authors: Nguyen Tuyen Duong Thanh , Wang Yan , Bui Tuyen N. , Lazcano Rossana , Ingram Davis R. , Yi Min , Vakulabharanam Varshini , Luo Linjie , Pina Marc A. , Karakas Cansu , Li Mi , Kettner Nicole M. , Somaiah Neeta , Hougton Peter J. , Mawlawi Osama , Lazar Alexander J. , Hunt Kelly K. , Keyomarsi Khandan
Published: March 2023

Abstract
Treatment strategies with a strong scientific rationale based on specific biomarkers are needed to improve outcomes in patients with advanced sarcomas. Suppression of cell-cycle progression through reactivation of the tumor suppressor retinoblastoma (Rb) using CDK4/6 inhibitors is a potential avenue for novel targeted therapies in sarcomas that harbor intact Rb signaling. Here, we evaluated combination treatment strategies (sequential and concomitant) with the CDK4/6 inhibitor abemacicib to identify optimal combination strategies. Expression of Rb was examined in 1,043 sarcoma tumor specimens, and 50% were found to be Rb-positive. Using in vitro and in vivo models, an effective two-step sequential combination strategy was developed. Abemaciclib was used first to prime Rb-positive sarcoma cells to reversibly arrest in G1 phase. Upon drug removal, cells synchronously traversed to S phase, where a second treatment with S-phase targeted agents (gemcitabine or Wee1 kinase inhibitor) mediated a synergistic response by inducing DNA damage. The response to treatment could be noninvasively monitored using real-time positron emission tomography imaging and serum thymidine kinase activity. Collectively, these results show that a novel, sequential treatment strategy with a CDK4/6 inhibitor followed by a DNA-damaging agent was effective, resulting in synergistic tumor cell killing. This approach can be readily translated into a clinical trial with noninvasive functional imaging and serum biomarkers as indicators of response and cell cycling.
Significance:
An innovative sequential therapeutic strategy targeting Rb, followed by treatment with agents that perturb DNA synthesis pathways, results in synergistic killing of Rb-positive sarcomas that can be noninvasively monitored.
Data from A Cell-Fate Reprogramming Strategy Reverses Epithelial-to-Mesenchymal Transition of Lung Cancer Cells While Avoiding Hybrid States
Authors: Kim Namhee , Hwang Chae Young , Kim Taeyoung , Kim Hyunjin , Cho Kwang-Hyun
Published: March 2023

Abstract
The epithelial-to-mesenchymal transition (EMT) of primary cancer contributes to the acquisition of lethal properties, including metastasis and drug resistance. Blocking or reversing EMT could be an effective strategy to improve cancer treatment. However, it is still unclear how to achieve complete EMT reversal (rEMT), as cancer cells often transition to hybrid EMT states with high metastatic potential. To tackle this problem, we employed a systems biology approach and identified a core-regulatory circuit that plays the primary role in driving rEMT without hybrid properties. Perturbation of any single node was not sufficient to completely revert EMT. Inhibition of both SMAD4 and ERK signaling along with p53 activation could induce rEMT in cancer cells even with TGFβ stimulation, a primary inducer of EMT. Induction of rEMT in lung cancer cells with the triple combination approach restored chemosensitivity. This cell-fate reprogramming strategy based on attractor landscapes revealed potential therapeutic targets that can eradicate metastatic potential by subverting EMT while avoiding hybrid states.
Significance:
Network modeling unravels the highly complex and plastic process regulating epithelial and mesenchymal states in cancer cells and discovers therapeutic interventions for reversing epithelial-to-mesenchymal transition and enhancing chemosensitivity.
Data from HBx-Induced HSPA8 Stimulates HBV Replication and Suppresses Ferroptosis to Support Liver Cancer Progression
Authors: Wang Yufei , Zhao Man , Zhao Lina , Geng Yu , Li Guanghao , Chen Lin , Yu Jingxuan , Yuan Hongfeng , Zhang Huihui , Yun Haolin , Yuan Ying , Wang Guowen , Feng Jinyan , Xu Liang , Wang Shuai , Hou Chunyu , Yang Guang , Zhang Ningning , Lu Wei , Zhang Xiaodong
Published: March 2023

Abstract
Hepatitis B virus (HBV) infection is a major driver of hepatocarcinogenesis. Ferroptosis is a type of iron-mediated cell death that can suppress liver transformation. Previous studies have linked HBV to ferroptosis in liver fibrosis and acute liver failure. However, whether ferroptosis is involved in HBV-mediated liver cancer is poorly understood. Here, we identified heat shock protein family A member 8 (HSPA8) as a crucial host factor that modulates HBV replication and ferroptosis in liver cancer. Hepatitis B X protein (HBx) upregulated HSPA8 by coactivating the transcription factor heat shock factor 1 (HSF1) in cells. HSPA8 enhanced HBV replication by recruiting hepatitis B core protein (HBc) to the HBV covalently closed circular DNA (cccDNA) minichromosome, forming a positive feedback loop. Moreover, HSPA8 suppressed ferroptosis in liver cancer cells by upregulating the expression of SLC7A11/GPX4 and decreasing erastin-mediated reactive oxygen species and Fe2+ accumulation in cells in vitro and in vivo. Inhibition of HSPA8 reduced the growth of HBV-positive liver tumors and increased sensitivity to erastin. In conclusion, HBx-elevated HSPA8 regulates both HBV replication and ferroptosis in liver cancer. Targeting HSPA8 could be a promising strategy for controlling HBV and hepatocarcinogenesis.
Significance:
HBV-induced upregulation of HSPA8 promotes hepatocarcinogenesis by suppressing ferroptosis and stimulating HBV replication, identifying HSPA8 as a potential therapeutic target in liver cancer.
Data from CircPDIA4 Induces Gastric Cancer Progression by Promoting ERK1/2 Activation and Enhancing Biogenesis of Oncogenic circRNAs
Authors: Shen Yue , Zhang Nasha , Chai Jie , Wang Teng , Ma Chi , Han Linyu , Yang Ming
Published: March 2023

Abstract
Circular RNAs (circRNA) are a group of noncoding, covalently uninterrupted loop transcripts, most of which remain to be functionally characterized. Here, we identified circPDIA4 as an oncogenic circRNA in gastric cancer. Clinically, circPDIA4 was significantly upregulated in malignant tissues and was associated with poor survival of patients with gastric cancer. The biogenesis of circPDIA4 was mediated by the RNA-binding protein Quaking, which bound introns 2 and 4 of PDIA4 pre-mRNA to promote backsplicing of exons 3 and 4. Elevated expression of circPDIA4 promoted distant metastasis in various mouse xenograft models in vivo and accelerated cancer cell invasion in vitro. CircPDIA4 functioned through distinct oncogenic mechanisms in the cytoplasm and the nucleus. Cytoplasmic circPDIA4 bound to ERK1/2 and sustained hyperactivation of the MAPK pathway by preventing DUSP6-mediated ERK1/2 dephosphorylation. Notably, circPDIA4 depletion enhanced the sensitivity of gastric cancer cells to ERK inhibitors. In the nucleus, circPDIA4 interacted with DHX9 as a decoy and repressed its inhibitory functions on circRNA biogenesis to boost expression of multiple oncogenic circRNAs, which promoted gastric cancer progression. These findings reveal a dual tumor-promoting mechanism for circPDIA4 by regulating oncogenic circRNA biogenesis and increasing MAPK activity. CircPDIA4 should be investigated further as a potential prognostic biomarker and therapeutic target in gastric cancer.
Significance:
Quaking-regulated circPDIA4 mediates different mechanisms in the nucleus and cytoplasm that coordinate to promote progression and drug resistance in gastric cancer.
Supplementary Methods, References, Legends for Table 1 and Figure 1 from Gender Disparities in the Tumor Genetics and Clinical Outcome of Multiple Myeloma
Authors: Boyd Kevin D. , Ross Fiona M. , Chiecchio Laura , Dagrada GianPaolo , Konn Zoe J. , Tapper William J. , Walker Brian A. , Wardell Christopher P. , Gregory Walter M. , Szubert Alex J. , Davies Faith E. , Morgan Gareth J.
Published: March 2023

Supplementary Methods, References, Legends for Table 1 and Figure 1 from Gender Disparities in the Tumor Genetics and Clinical Outcome of Multiple Myeloma
Supplementary Tables 1-2 from Exposure to Smoking Imagery in the Movies and Experimenting with Cigarettes among Mexican Heritage Youth
Authors: Wilkinson Anna V. , Spitz Margaret R. , Prokhorov Alexander V. , Bondy Melissa L. , Shete Sanjay , Sargent James D.
Published: March 2023

Supplementary Tables 1-2 from Exposure to Smoking Imagery in the Movies and Experimenting with Cigarettes among Mexican Heritage Youth
Supplementary Table 1 from Tumor and Salivary Matrix Metalloproteinase Levels Are Strong Diagnostic Markers of Oral Squamous Cell Carcinoma
Authors: Stott-Miller Marni , Houck John R. , Lohavanichbutr Pawadee , Méndez Eduardo , Upton Melissa P. , Futran Neal D. , Schwartz Stephen M. , Chen Chu
Published: March 2023

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Supplemental Figures from Prediagnostic Circulating Anti-Müllerian Hormone Concentrations Are Not Associated with Prostate Cancer Risk
Authors: Sklavos Martha M. , Zhou Cindy Ke , Pinto Ligia A. , Cook Michael B.
Published: March 2023

Supplemental Figures. Supplemental Figure 1. AMH distribution for cases and controls. Supplemental Figure 2. AMH levels in all participants stratified by 5 year age groups.
Supplementary Table 4 from Common Polymorphisms in the Adiponectin and Its Receptor Genes, Adiponectin Levels and the Risk of Prostate Cancer
Authors: Dhillon Preet K. , Penney Kathryn L. , Schumacher Fredrick , Rider Jennifer R. , Sesso Howard D. , Pollak Michael , Fiorentino Michelangelo , Finn Stephen , Loda Massimo , Rifai Nader , Mucci Lorelei A. , Giovannucci Edward , Stampfer Meir J. , Ma Jing
Published: March 2023

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Data Supplement from A Risk Prediction Model for Smoking Experimentation in Mexican American Youth
Authors: Talluri Rajesh , Wilkinson Anna V. , Spitz Margaret R. , Shete Sanjay
Published: March 2023

Supplementary Table S1. Univariate analysis of the smoking experimentation risk factors that were significant at the 0.05 level of significance (sorted by decreasing significance). Supplementary Table S2: Descriptions of the predictors presented in Table S1. Supplementary Figure S1: ROC curves for 1 to 5-year risk of smoking experimentation.
Hypothesis/Commentary for This Article from Demographic Disparities in Patterns of Care and Survival Outcomes for Patients with Resected Gastric Adenocarcinoma
Authors: Stessin Alexander M. , Sherr David L.
Published: March 2023

Hypothesis/Commentary for This Article from Demographic Disparities in Patterns of Care and Survival Outcomes for Patients with Resected Gastric Adenocarcinoma
Supplementary Figure 1 from Relationship between Epidermal Growth Factor Receptor Status, p16INK4A, and Outcome in Head and Neck Squamous Cell Carcinoma
Authors: Young Richard J. , Rischin Danny , Fisher Richard , McArthur Grant A. , Fox Stephen B. , Peters Lester J. , Corry June , Lim Annette , Waldeck Kelly , Solomon Benjamin
Published: March 2023

Supplementary Figure 1 from Relationship between Epidermal Growth Factor Receptor Status, p16INK4A, and Outcome in Head and Neck Squamous Cell Carcinoma
Supplementary Table 4 from Distribution and Hepatocellular Carcinoma–Related Viral Properties of Hepatitis B Virus Genotypes in Mainland China: A Community-Based Study
Authors: Yin Jianhua , Zhang Hongwei , He Yongchao , Xie Jiaxin , Liu Shijian , Chang Wenjun , Tan Xiaojie , Gu Chunying , Lu Wei , Wang Hongyang , Bi Shengli , Cui Fuqiang , Liang Xiaofeng , Schaefer Stephan , Cao Guangwen
Published: March 2023

Supplementary Table 4 from Distribution and Hepatocellular Carcinoma–Related Viral Properties of Hepatitis B Virus Genotypes in Mainland China: A Community-Based Study
Adobe PDF - EPI-11-0061R_DeSantis_supp_table_1.pdf from Breast Cancer Incidence Rates in U.S. Women Are No Longer Declining
Authors: DeSantis Carol , Howlader Nadia , Cronin Kathleen A. , Jemal Ahmedin
Published: March 2023

Adobe PDF - EPI-11-0061R_DeSantis_supp_table_1.pdf from Breast Cancer Incidence Rates in U.S. Women Are No Longer Declining
Supplementary Tables 1-4 from Collagen XXIII: A Potential Biomarker for the Detection of Primary and Recurrent Non–Small Cell Lung Cancer
Authors: Spivey Kristin A. , Banyard Jacqueline , Solis Luisa M. , Wistuba Ignacio I. , Barletta Justine A. , Gandhi Leena , Feldman Henry A. , Rodig Scott J. , Chirieac Lucian R. , Zetter Bruce R.
Published: March 2023

Supplementary Tables 1-4 from Collagen XXIII: A Potential Biomarker for the Detection of Primary and Recurrent Non–Small Cell Lung Cancer
Supplementary Figure Legends from Cigarette Smoking and Pulmonary Function in Adult Survivors of Childhood Cancer Exposed to Pulmonary-Toxic Therapy: Results from the St. Jude Lifetime Cohort Study
Authors: Oancea S. Cristina , Gurney James G. , Ness Kirsten K. , Ojha Rohit P. , Tyc Vida L. , Klosky James L. , Srivastava DeoKumar , Stokes Dennis C. , Robison Leslie L. , Hudson Melissa M. , Green Daniel M.
Published: March 2023

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Supplementary Figure 5 from Global Patterns of Cancer Incidence and Mortality Rates and Trends
Authors: Jemal Ahmedin , Center Melissa M. , DeSantis Carol , Ward Elizabeth M.
Published: March 2023

Supplementary Figure 5 from Global Patterns of Cancer Incidence and Mortality Rates and Trends
Supplementary Figure 1 from Global Patterns of Cancer Incidence and Mortality Rates and Trends
Authors: Jemal Ahmedin , Center Melissa M. , DeSantis Carol , Ward Elizabeth M.
Published: March 2023

Supplementary Figure 1 from Global Patterns of Cancer Incidence and Mortality Rates and Trends
Supplemental Table 2 from Sex Steroid Hormone Metabolism in Relation to Risk of Aggressive Prostate Cancer
Authors: Black Amanda , Pinsky Paul F. , Grubb Robert L. , Falk Roni T. , Hsing Ann W. , Chu Lisa , Meyer Tamra , Veenstra Timothy D. , Xu Xia , Yu Kai , Ziegler Regina G. , Brinton Louise A. , Hoover Robert N. , Cook Michael B.
Published: March 2023

Risk of aggressive prostate cancer according to cross-classified tertiles of estradiol and testosterone.
Supplementary Table 1 from Analytic Variability in Immunohistochemistry Biomarker Studies
Authors: Anagnostou Valsamo K. , Welsh Allison W. , Giltnane Jennifer M. , Siddiqui Summar , Liceaga Camil , Gustavson Mark , Syrigos Konstantinos N. , Reiter Jill L. , Rimm David L.
Published: March 2023

Supplementary Table 1 from Analytic Variability in Immunohistochemistry Biomarker Studies
Supplementary Tables 1-3 from Folate Intake along with Genetic Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase in Patients with Advanced Gastric Cancer
Authors: Shitara Kohei , Muro Kei , Ito Seiji , Sawaki Akira , Tajika Masahiro , Kawai Hiroki , Yokota Tomoya , Takahari Daisuke , Shibata Takashi , Ura Takashi , Ito Hidemi , Hosono Satoyo , Kawase Takakazu , Watanabe Miki , Tajima Kazuo , Yatabe Yasushi , Tanaka Hideo , Matsuo Keitaro
Published: March 2023

Supplementary Tables 1-3 from Folate Intake along with Genetic Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase in Patients with Advanced Gastric Cancer
Supplementary Tables 1-2 from Chromosome 3p12.3-p14.2 and 3q26.2-q26.32 Are Genomic Markers for Prognosis of Advanced Nasopharyngeal Carcinoma
Authors: Sheu Jim Jinn-Chyuan , Lee Chia-Huei , Ko Jenq-Yuh , Tsao George S.W. , Wu Chung-Chun , Fang Chih-Yeu , Tsai Fuu-Jen , Hua Chun-Hung , Chen Chi-Long , Chen Jen-Yang
Published: March 2023

Supplementary Tables 1-2 from Chromosome 3p12.3-p14.2 and 3q26.2-q26.32 Are Genomic Markers for Prognosis of Advanced Nasopharyngeal Carcinoma
Supplementary Table S2 from HPV Seroconversion Following Anal and Penile HPV Infection in HIV-Negative and HIV-Infected MSM
Authors: Mooij Sofie H. , Landén Olivia , van der Klis Fiona R.M. , van der Sande Marianne A.B. , de Melker Hester E. , Xiridou Maria , van Eeden Arne , Heijman Titia , Speksnijder Arjen G.C.L. , Snijders Peter J.F. , Schim van der Loeff Maarten F.
Published: March 2023

Supplementary Table S2. Multivariable associations between anal and penile HPV infection and type-specific seroconversion, additionally adjusted for CD4 cell count and HIV viral load.
Supplementary Table S1 from HPV Seroconversion Following Anal and Penile HPV Infection in HIV-Negative and HIV-Infected MSM
Authors: Mooij Sofie H. , Landén Olivia , van der Klis Fiona R.M. , van der Sande Marianne A.B. , de Melker Hester E. , Xiridou Maria , van Eeden Arne , Heijman Titia , Speksnijder Arjen G.C.L. , Snijders Peter J.F. , Schim van der Loeff Maarten F.
Published: March 2023

Supplementary Table S1. Associations between anal and penile HPV infection and type-specific seroconversion, using the stricter definition of seroconversion.
Data Supplement from Sun Exposure and Melanoma Survival: A GEM Study
Authors: Berwick Marianne , Reiner Anne S. , Paine Susan , Armstrong Bruce K. , Kricker Anne , Goumas Chris , Cust Anne E. , Thomas Nancy E. , Groben Pamela A. , From Lynn , Busam Klaus , Orlow Irene , Marrett Loraine D. , Gallagher Richard P. , Gruber Stephen B. , Anton-Culver Hoda , Rosso Stefano , Zanetti Roberto , Kanetsky Peter A. , Dwyer Terry , Venn Alison , Lee-Taylor Julia , Begg Colin B.
Published: March 2023

Supplementary Table S3. Average annual sun exposure in relationship to melanoma survival, adjusting for Breslow thickness.
Supplementary Tables 1-2 from Genetic Variation in TYMS in the One-Carbon Transfer Pathway Is Associated with Ovarian Carcinoma Types in the Ovarian Cancer Association Consortium
Authors: Kelemen Linda E. , Goodman Marc T. , McGuire Valerie , Rossing Mary Anne , Webb Penelope M. , Köbel Martin , Anton-Culver Hoda , Beesley Jonathan , Berchuck Andrew , Brar Sony , Carney Michael E. , Chang-Claude Jenny , Chenevix-Trench Georgia , Cramer Daniel W. , Cunningham Julie M. , DiCioccio Richard A. , Doherty Jennifer A. , Easton Douglas F. , Fredericksen Zachary S. , Fridley Brooke L. , Gates Margaret A. , Gayther Simon A. , Gentry-Maharaj Aleksandra , Høgdall Estrid , Kjær Susanne Krüger , Lurie Galina , Menon Usha , Moorman Patricia G. , Moysich Kirsten , Ness Roberta B. , Palmieri Rachel T. , Pearce Celeste L. , Pharoah Paul D.P. , Ramus Susan J. , Song Honglin , Stram Daniel O. , Tworoger Shelley S. , Van Den Berg David , Vierkant Robert A. , Wang-Gohrke Shan , Whittemore Alice S. , Wilkens Lynne R. , Wu Anna H. , Schildkraut Joellen M. , Sellers Thomas A. , Goode Ellen L.
Published: March 2023

Supplementary Tables 1-2 from Genetic Variation in TYMS in the One-Carbon Transfer Pathway Is Associated with Ovarian Carcinoma Types in the Ovarian Cancer Association Consortium
Supplementary Tables 1-3 from A Sex-Specific Association between a 15q25 Variant and Upper Aerodigestive Tract Cancers
Authors: Chen Dan , Truong Therese , Gaborieau Valerie , Byrnes Graham , Chabrier Amelie , Chuang Shu-chun , Olshan Andrew F. , Weissler Mark C. , Luo Jingchun , Romkes Marjorie , Buch Shama , Nukui Tomoko , Franceschi Silvia , Herrero Rolando , Talamini Renato , Kelsey Karl T. , Christensen Brock , McClean Michael D. , Lacko Martin , Manni Johannes J. , Peters Wilbert H. M. , Lubiński Jan , Trubicka Joanna , Lener Marcin , Muscat Joshua E. , Lazarus Philip , Wei Qingyi , Sturgis Erich M. , Zhang Zuo-Feng , Chang Shen-Chih , Wang Renyi , Schwartz Stephen M. , Chen Chu , Benhamou Simone , Lagiou Pagona , Holcátová Ivana , Richiardi Lorenzo , Kjaerheim Kristina , Agudo Antonio , Castellsagué Xavier , Macfarlane Tatiana V. , Barzan Luigi , Canova Cristina , Thakker Nalin S. , Conway David I. , Znaor Ariana , Healy Claire M. , Ahrens Wolfgang , Zaridze David , Szeszenia-Dabrowska Neonila , Lissowska Jolanta , Fabianova Eleonora , Bucur Alexandru , Bencko Vladimir , Foretova Lenka , Janout Vladimir , Curado Maria Paula , Koifman Sergio , Menezes Ana , Wünsch-Filho Victor , Eluf-Neto José , Fernandez Leticia , Boccia Stefania , Hashibe Mia , Hayes Richard B. , Boffetta Paolo , Brennan Paul , McKay James D.
Published: March 2023

Supplementary Tables 1-3 from A Sex-Specific Association between a 15q25 Variant and Upper Aerodigestive Tract Cancers
Editorial for this Article from Men with Low Serum Cholesterol Have a Lower Risk of High-Grade Prostate Cancer in the Placebo Arm of the Prostate Cancer Prevention Trial
Authors: Platz Elizabeth A. , Till Cathee , Goodman Phyllis J. , Parnes Howard L. , Figg William D. , Albanes Demetrius , Neuhouser Marian L. , Klein Eric A. , Thompson Ian M. , Kristal Alan R.
Published: March 2023

Editorial for this Article from Men with Low Serum Cholesterol Have a Lower Risk of High-Grade Prostate Cancer in the Placebo Arm of the Prostate Cancer Prevention Trial
Supplementary Table 2 from Variation in TP63 is Associated with Lung Adenocarcinoma in the UK Population
Authors: Wang Yufei , Broderick Peter , Matakidou Athena , Vijayakrishnan Jayaram , Eisen Timothy , Houlston Richard S.
Published: March 2023

Supplementary Table 2 from Variation in TP63 is Associated with Lung Adenocarcinoma in the UK Population
Supplementary Table 4 from Smoking at Diagnosis Is an Independent Prognostic Factor for Cancer-Specific Survival in Head and Neck Cancer: Findings from a Large, Population-Based Study
Authors: Sharp Linda , McDevitt Joseph , Carsin Anne-Elie , Brown Christopher , Comber Harry
Published: March 2023

Supplementary table 4: supplemental analysis, Cox model for all head and neck cancers
Supplementary Figure 1 from Circulating Markers of Interstitial Lung Disease and Subsequent Risk of Lung Cancer
Authors: Shiels Meredith S. , Chaturvedi Anil K. , Katki Hormuzd A. , Gochuico Bernadette R. , Caporaso Neil E. , Engels Eric A.
Published: March 2023

Supplementary Figure 1 from Circulating Markers of Interstitial Lung Disease and Subsequent Risk of Lung Cancer