bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Oxidative phosphorylation fueled by fatty acid oxidation sensitizes leukemic stem cells to cold
Authors: Griessinger Emmanuel , Pereira-Martins Diego , Nebout Marielle , Bosc Claudie , Saland Estelle , Boet Emeline , Sahal Ambrine , Chiche Johanna , Debayle Delphine , Fleuriot Lucile , Pruis Maurien , Mansat-De Mas Veronique , Vergez Francois , Récher Christian , Huls Gerwin , Sarry Jean-Emmanuel , Schuringa Jan Jacob , Peyron Jean-François
Published: September 2024

Abstract
Dependency on mitochondrial oxidative phosphorylation (OxPhos) is a potential weakness for leukemic stem cells (LSCs) that can be exploited for therapeutic purposes. Fatty acid oxidation (FAO) is a crucial OxPhos-fueling catabolic pathway for some acute myeloid leukemia (AML) cells, particularly chemotherapy-resistant AML cells. Here, we identified cold sensitivity at 4°C (cold killing challenge; CKC4), commonly used for sample storage, as a novel vulnerability that selectively kills AML LSCs with active FAO-supported OxPhos while sparing normal hematopoietic stem cells (HSCs). Cell death of OxPhos-positive leukemic cells was induced by membrane permeabilization at 4°C; by sharp contrast, leukemic cells relying on glycolysis were resistant. Forcing glycolytic cells to activate OxPhos metabolism sensitized them to CKC4. Lipidomic and proteomic analyzes showed that OxPhos shapes the composition of the plasma membrane and introduces variation of 22 lipid subfamilies between cold-sensitive and cold-resistant cells. Together, these findings indicate that steady-state energy metabolism at body temperature predetermines the sensitivity of AML LSCs to cold temperature, suggesting that cold sensitivity could be a potential OxPhos biomarker. These results could have important implications for designing experiments for AML research to avoid cell storage at 4°C.
Data from Characterizing evolutionary dynamics reveals strategies to exhaust the spectrum of subclonal resistance in EGFR-mutant lung cancer
Authors: Müller Nina , Lorenz Carina , Ostendorp Jenny , Heisel Felix S. , Friese Ulrich P. , Cartolano Maria , Plenker Dennis , Tumbrink Hannah L. , Heimsoeth Alena , Baedeker Philipp , Ortiz-Cuaran Sandra , Weiss Jonathan , Büttner Reinhard , Peifer Martin , Thomas Roman K. , Sos Martin L. , Berg Johannes , Brägelmann Johannes
Published: September 2024

Abstract
The emergence of resistance to targeted therapies restrains their efficacy. The development of rational-ly guided drug combinations could overcome this currently insurmountable clinical challenge. However, our limited understanding of the trajectories that drive the outgrowth of resistant clones in cancer cell populations precludes design of drug combinations to forestall resistance. Here, we propose an iterative treatment strategy coupled with genomic profiling and genome-wide CRISPR activation screening to systematically extract and define pre-existing resistant subpopulations in an EGFR-driven lung cancer cell line. Integrating these modalities identifies several resistance mechanisms, including activation of YAP/TAZ signaling by WWTR1 amplification, and estimated the associated cellular fitness for mathematical population modeling. These observations led to the development of a combina-tion therapy that eradicated resistant clones in large cancer cell line populations by exhausting the spectrum of genomic resistance mechanisms. However, a small fraction of cancer cells was able to enter a reversible non-proliferative state of drug tolerance. This sub-population exhibited mesenchy-mal properties, NRF2 target gene expression and sensitivity to ferroptotic cell death. Exploiting this induced collateral sensitivity by GPX4 inhibition clears drug tolerant populations and led to tumor cell eradication. Overall, this experimental in vitro data and theoretical modeling demonstrate why targeted mono- and dual therapies will likely fail in sufficiently large cancer cell populations to limit long-term efficacy. Our approach is not tied to a particular driver mechanism and can be used to systematically assess and ideally exhaust the resistance landscape for different cancer types to rationally design com-bination therapies.
Data from Proteasome Inhibition Sensitizes Liposarcoma to MDM2 Inhibition with Nutlin-3 by Activating the ATF4/CHOP Stress Response Pathway
Authors: Ludwig Michael P. , Galbraith Matthew D. , Eduthan Neetha Paul. , Hill Amanda A. , Clay Michael R. , Moreno Tellez Cristiam , Wilky Breelyn A. , Elias Anthony , Espinosa Joaquín Maximiliano. , Sullivan Kelly D.
Published: September 2024

Abstract
Liposarcoma is the most commonly occurring soft tissue sarcoma and is frequently characterized by amplification of chromosome region 12q13-15 harboring the oncogenes MDM2 and CDK4. This unique genetic profile makes liposarcoma an attractive candidate for targeted therapeutics. While CDK4/6 inhibitors are currently employed for treatment of several cancers, MDM2 inhibitors have yet to attain clinical approval. Here, we report the molecular characterization of the response of liposarcoma to the MDM2 inhibitor nutlin-3. Treatment with nutlin-3 led to upregulation of two nodes of the proteostasis network: the ribosome and the proteasome. CRISPR/Cas9 was used to perform a genome-wide loss of function screen that identified PSMD9, which encodes a proteasome subunit, as a regulator of response to nutlin-3. Accordingly, pharmacological studies with a panel of proteasome inhibitors revealed strong combinatorial induction of apoptosis with nutlin-3. Mechanistic studies identified activation of the ATF4/CHOP stress response axis as a potential node of interaction between nutlin-3 and the proteasome inhibitor carfilzomib. CRISPR/Cas9 gene editing experiments confirmed that ATF4, CHOP, and the BH3-only protein, NOXA, are all required for nutlin-3 and carfilzomib-induced apoptosis. Furthermore, activation of the unfolded protein response using tunicamycin and thapsigargin was sufficient to activate the ATF4/CHOP stress response axis and sensitize to nutlin-3. Finally, cell line and patient-derived xenograft models demonstrated combinatorial effects of treatment with idasanutlin and carfilzomib on liposarcoma growth in vivo. Together, these data indicate that targeting of the proteasome could improve the efficacy of MDM2 inhibitors in liposarcoma.
Data from Deficiency of the Polycomb protein RYBP and TET methylcytosine oxidases promotes extensive CpG island hypermethylation and malignant transformation
Authors: Cui Wei , Huang Zhijun , Jin Seung-Gi , Johnson Jennifer , Lau Kin H. , Hostetter Galen , Pfeifer Gerd P.
Published: September 2024

Abstract
Hypermethylation of CpG islands is a common feature of cancer cells and predominantly affects Polycomb-associated genomic regions. Elucidating the underlying mechanisms leading to DNA hypermethylation in human cancer could help identify chemoprevention strategies. Here, we evaluated the role of Polycomb complexes and 5-methylcytosine oxidases in protecting CpG islands from DNA methylation and observed that four genes coding for components of Polycomb repressive complex 1 (PRC1) are downregulated in tumors. Inactivation of RYBP, a key activator of variant PRC1 complexes, in combination with all three 5-methylcytosine oxidases (TET proteins) in nontumorigenic bronchial epithelial cells led to widespread hypermethylation of Polycomb-marked CpG islands affecting almost 4,000 target genes, which closely resembled the DNA hypermethylation landscape observed in human squamous cell lung tumors. The RYBP- and TET-deficient cells showed methylation-associated aberrant regulation of cancer-relevant pathways, including defects in the Hippo tumor suppressor network. Notably, the quadruple knockout cells acquired a transformed phenotype, including anchorage-independent growth and formation of squamous cell carcinomas in mice. This work provides a mechanism promoting hypermethylation of CpG islands and shows that such hypermethylation can lead to cell transformation. The breakdown of a two-pronged protection mechanism can be a route towards genome-wide hypermethylation of CpG islands in tumors.
Data from The mTOR Signaling Pathway Interacts with the ER Stress Response and the Unfolded Protein Response in Cancer
Authors: Mafi Sahar , Ahmadi Elham , Meehan Eileen , Chiari Conner , Mansoori Behzad , Sadeghi Hossein , Milani Sahar , Jafarinia Morteza , Taeb Shahram , Mafakheri Bashmagh Bayan , Mansoorian Seyed Mohammad Ali. , Soltani-Zangbar Mohammad Sadegh , Wang Kepeng , Rostamzadeh Davoud
Published: September 2024

Abstract
The mTOR complex 1 (mTORC1) coordinates several important environmental and intracellular cues to control a variety of biological processes, such as cell growth, survival, autophagy, and metabolism in response to energy levels, growth signals, and nutrients. The endoplasmic reticulum (ER) is a crucial intracellular organelle that is essential for numerous cellular functions, including the synthesis, folding and modification of newly synthesized proteins, stress responsiveness, and maintainence of cellular homeostasis. mTOR-mediated upregulation of protein synthesis induces the accumulation of misfolded or unfolded proteins in the ER lumen which induces ER stress, leading to activation of the unfolded protein response (UPR) pathway. Reciprocally, ER stress regulates the PI3K/AKT/mTOR signaling pathway. Therefore, under pathological conditions, the crosstalk between the mTOR and UPR signaling pathways during cellular stress can critically affect cancer cell fate and may be involved in the pathogenesis and therapeutic outcome of cancer. Here, we discuss accumulating evidence showing the mechanism of action, interconnections, and molecular links between mTOR signaling and ER stress in tumorigenesis and highlight potential therapeutic implications for numerous cancers.
Data from Alpha-1 adrenergic antagonists sensitize neuroblastoma to therapeutic differentiation
Authors: Broso Francesca , Gatto Pamela , Sidarovich Viktoryia , Ambrosini Chiara , De Sanctis Veronica , Bertorelli Roberto , Zaccheroni Elena , Ricci Benedetta , Destefanis Eliana , Longhi Sara , Sebastiani Enrico , Tebaldi Toma , Adami Valentina , Quattrone Alessandro
Published: September 2024

Abstract
Neuroblastoma (NB) is an aggressive childhood tumor, with high-risk cases having a 5-year overall survival probability of approximately 50%. The multimodal therapeutic approach for NB includes treatment with the retinoid isotretinoin (13-cis retinoic acid; 13cRA), which is used in the post-consolidation phase as an anti-proliferation and pro-differentiation agent to minimize residual disease and prevent relapse. Through small molecule screening, we identified isorhamnetin (ISR) as a synergistic compound with 13cRA in inhibiting up to 80% of NB cell viability. The synergistic effect was accompanied by a marked increase in the expression of the adrenergic receptor α1B (ADRA1B) gene. Genetic knockout of ADRA1B or its specific blockade using ɑ1/ɑ1B adrenergic antagonists led to selective sensitization of MYCN-amplified NB cells to cell viability reduction and neural differentiation induced by 13cRA, thus mimicking ISR activity. Administration of doxazosin, a safe α1-antagonist used in pediatric patients, in combination with 13cRA in NB xenografted mice exerted marked control of tumor growth, while each drug alone was ineffective. Overall, this study identified the α1B adrenergic receptor as a pharmacological target in NB, supporting the evaluation of adding α1-antagonists to the post-consolidation therapy of NB to more efficiently control residual disease.
Data from The EstroGene database reveals diverse temporal, context-dependent, and bidirectional estrogen receptor regulomes in breast cancer
Authors: Li Zheqi , Li Tianqin , Yates Megan E. , Wu Yang , Ferber Amanda , Chen Lyuqin , Brown Daniel D. , Carroll Jason S. , Sikora Matthew J. , Tseng George C. , Oesterreich Steffi , Lee Adrian V.
Published: September 2024

Abstract
As one of the most successful cancer therapeutic targets, estrogen receptor-α (ER/ESR1) has been extensively studied over the past few decades. Sequencing technological advances have enabled genome-wide analysis of ER action. However, comparison of individual studies is limited by different experimental designs, and few meta-analyses are available. Here, we established the EstroGene database through unified processing of data from 246 experiments including 136 transcriptomic, cistromic, and epigenetic datasets focusing on estradiol (E2)-triggered ER activation across 19 breast cancer cell lines. A user-friendly browser (https://estrogene.org/) was generated for multi-omic data visualization involving gene inquiry under user-defined experimental conditions and statistical thresholds. Notably, annotation of metadata associated with public datasets revealed a considerable lack of experimental details. Comparison of independent RNA-seq or ER ChIP-seq data with the same design showed large variability and only strong effects could be consistently detected. Temporal estrogen response metasignatures were defined, and the association of E2 response rate with temporal transcriptional factors, chromatin accessibility, and heterogeneity of ER expression was evaluated. Unexpectedly, harmonizing 146 E2-induced transcriptomic datasets uncovered a subset of genes harboring bidirectional E2-regulation, which was linked to unique transcriptional factors and highly associated with immune surveillance in the clinical setting. Furthermore, the context dependent E2 response programs were characterized in MCF7 and T47D cell lines, the two most frequently used models in the EstroGene database. Collectively, the EstroGene database provides an informative and practical resource to the cancer research community to uniformly evaluate key reproducible features of ER regulomes and unravels modes of ER signaling.
Data from Activation of the cGAS/STING axis in genome-damaged hematopoietic cells does not impact blood cell formation or leukemogenesis
Authors: Dressel Nicole , Natusch Loreen , Munz Clara M. , Costas Ramon Santiago , Morcos Mina N.F. , Loff Anja , Hiller Björn , Haase Christa , Schulze Livia , Müller Patrick , Lesche Mathias , Dahl Andreas , Luksch Hella , Roesen-Wolff Angela , Roers Axel , Behrendt Rayk , Gerbaulet Alexander
Published: September 2024

Abstract
Genome damage is a main driver of malignant transformation, but it also induces aberrant inflammation via the cGAS/STING DNA sensing pathway. Activation of cGAS/STING can trigger cell death and senescence, thereby potentially eliminating genome-damaged cells and preventing against malignant transformation. Here, we report that defective ribonucleotide excision repair (RER) in the hematopoietic system caused genome instability with concomitant activation of the cGAS/STING axis and compromised hematopoietic stem cell function, ultimately resulting in leukemogenesis. Additional inactivation of cGAS, STING, or type I IFN signaling, however, had no detectable effect on blood cell generation and leukemia development in RER-deficient hematopoietic cells. In wild-type mice, hematopoiesis under steady-state conditions and in response to genome damage was not affected by loss of cGAS. Together, this data challenges a role of the cGAS/STING pathway in protecting the hematopoietic system against DNA damage and leukemic transformation.
Data from Single-cell characterization of pulmonary nodules implicates suppression of immunosurveillance across early stages of lung adenocarcinoma
Authors: Yanagawa Jane , Tran Linh M. , Salehi-Rad Ramin , Lim Raymond J. , Dumitras Camelia , Fung Eileen , Wallace William D. , Prosper Ashley E. , Fishbein Gregory , Shea Conor , Hong Rui , Kahangi Bitta , Deng John J. , Gower Adam C. , Liu Bin , Campbell Joshua D. , Mazzilli Sarah A. , Beane Jennifer E. , Kadara Humam , Lenburg Marc E. , Spira Avrum E. , Aberle Denise R. , Krysan Kostyantyn , Dubinett Steven M.
Published: September 2024

Abstract
A greater understanding of molecular, cellular, and immunological changes during the early stages of lung adenocarcinoma development could improve diagnostic and therapeutic approaches in patients with pulmonary nodules at risk for lung cancer. To elucidate the immunopathogenesis of early lung tumorigenesis, we evaluated surgically resected pulmonary nodules representing the spectrum of early lung adenocarcinoma as well as associated normal lung tissues utilizing single-cell RNA sequencing and validated the results by flow cytometry and multiplex immunofluorescence. Single-cell transcriptomics revealed a significant decrease in gene expression associated with cytolytic activities of tumor-infiltrating natural killer and natural killer T cells. This was accompanied by a reduction in effector T cells and an increase of CD4+ regulatory T cells in subsolid nodules. An independent set of resected pulmonary nodules consisting of both adenocarcinomas and associated premalignant lesions corroborated the early increment of regulatory T cells in premalignant lesions compared to the associated normal lung tissues by multiplex immunofluorescence. Gene expression analysis indicated that cancer-associated alveolar type 2 cells and fibroblasts may contribute to the deregulation of the extracellular matrix, potentially affecting immune infiltration in subsolid nodules through ligand-receptor interactions. These findings suggest that there is a suppression of immune surveillance across the spectrum of early-stage lung adenocarcinoma.
Data from Abemaciclib is effective in palbociclib-resistant hormone receptor-positive metastatic breast cancers
Authors: Navarro-Yepes Juliana , Kettner Nicole M. , Rao Xiayu , Bishop Cassandra Santaella. , Bui Tuyen N. , Wingate Hannah F. , Singareeka Raghavendra Akshara , Wang Yan , Wang Jing , Sahin Aysegul A. , Meric-Bernstam Funda , Hunt Kelly K. , Damodaran Senthil , Tripathy Debu , Keyomarsi Khandan
Published: September 2024

Abstract
Cyclin-dependent-kinase-4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) is standard of care for patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC). However, resistance to CDK4/6is plus ET remains a clinical problem with limited therapeutic options following disease progression. Different CDK4/6is might have distinct mechanisms of resistance, and therefore using them sequentially or targeting their differentially altered pathways could delay disease progression. To understand pathways leading to resistance to the CDK4/6is palbociclib and abemaciclib, we generated multiple in vitro models of palbociclib-resistant (PR) and abemaciclib-resistant (AR) cell lines, as well as in vivo patient-derived xenografts (PDX) and ex vivo PDX-derived organoids from patients who progressed on CDK4/6i. PR and AR breast cancer cells exhibited distinct transcriptomic and proteomic profiles that sensitized them to different classes of inhibitors; PR cells upregulated G2/M pathways and responded to abemaciclib, while AR cells upregulated mediators of the oxidative phosphorylation pathway (OXPHOS) and responded to OXPHOS inhibitors. PDX and organoid models derived from palbociclib-resistant breast cancer patients remained responsive to abemaciclib. Resistance to palbociclib while maintaining sensitivity to abemaciclib was associated with pathway-specific transcriptional activity but was not associated with any individual genetic alterations. Lastly, data from a cohort of 52 patients indicated that patients with HR-positive/HER2-negative MBC who progressed on palbociclib-containing regimens can exhibit a meaningful overall clinical benefit from abemaciclib-based therapy when administered after palbociclib. These findings provide the rationale for clinical trials evaluating the benefit of abemaciclib treatment following progression on a prior CDK4/6i.
Data from Development of a rare earth nanoprobe enables in vivo real-time detection of sentinel lymph node metastasis of breast cancer using NIR-IIb imaging
Authors: Zhu Yuan-Yuan , Song Liang , Zhang Yong-Qu , Liu Wan-Ling , Chen Wei-Ling , Gao Wen-Liang , Zhang Li-Xin , Wang Jia-Zheng , Ming Zi-He , Zhang Yun , Zhang Guo-Jun
Published: September 2024

Abstract
Sentinel lymph node (SLN) biopsy plays a critical role in axillary staging of breast cancer. However, traditional SLN mapping does not accurately discern the presence or absence of metastatic disease. Detection of SLN metastasis largely hinges on examination of frozen sections or paraffin-embedded tissues post-SLN biopsy. To improve detection of SLN metastasis, we developed a second near-infrared (NIR-II) in vivo fluorescence imaging system, pairing erbium-based rare-earth nanoparticles (ErNPs) with bright down-conversion fluorescence at 1556 nm. To visualize SLNs bearing breast cancer, ErNPs were modified by balixafortide (ErNPs@POL6326), a peptide antagonist of the chemokine receptor CXCR4. The ErNPs@POL6326 probes readily drained into SLNs when delivered subcutaneously, entering metastatic breast tumor cells specifically via CXCR4-mediated endocytosis. NIR fluorescence signals increased significantly in tumor-positive versus tumor-negative SLNs, enabling accurate determination of SLN breast cancer metastasis. In a syngeneic mouse mammary tumor model and a human breast cancer xenograft model, sensitivity for SLN metastasis detection was 92.86% and 93.33%, respectively, and specificity was 96.15% and 96.08%, respectively. Of note, the probes accurately detected both macrometastases and micrometastases in SLNs. These results overall underscore the potential of ErNPs@POL6326 for real-time visualization of SLNs and in vivo screening for SLN metastasis.
Data from The ratio of key metabolic transcripts is a predictive biomarker of breast cancer metastasis to the lung
Authors: Mathur Deepti , Liao Chen , Lin Wendy , La Ferlita Alessandro , Alaimo Salvatore , Taylor Samuel , Zhong Yi , Iacobuzio-Donahue Christine , Ferro Alfredo , Xavier Joao B.
Published: September 2024

Abstract
Understanding the rewired metabolism underlying organ-specific metastasis in breast cancer could help identify strategies to improve the treatment and prevention of metastatic disease. Here, we used a systems biology approach to compare metabolic fluxes used by parental breast cancer cells and their brain- and lung-homing derivatives. Divergent lineages had distinct, heritable metabolic fluxes. Lung-homing cells maintained high glycolytic flux despite low levels of glycolytic intermediates, constitutively activating a pathway sink into lactate. This strong Warburg effect was associated with a high ratio of lactate dehydrogenase (LDH) to pyruvate dehydrogenase (PDH) expression, which correlated with lung metastasis in patients with breast cancer. While feature classification models trained on clinical characteristics alone were unable to predict tropism, the LDH/PDH ratio was a significant predictor of metastasis to the lung but not to other organs, independent of other transcriptomic signatures. High lactate efflux was also a trait in lung-homing metastatic pancreatic cancer cells, suggesting that lactate production may be a convergent phenotype in lung metastasis. Together, these analyses highlight the essential role that metabolism plays in organ-specific cancer metastasis and identify a putative biomarker for predicting lung metastasis in breast cancer patients.
Data from Oncogenic Calreticulin Induces Immune Escape by Stimulating TGFβ Expression and Regulatory T-cell Expansion in the Bone Marrow Microenvironment
Authors: Schmidt Dominik , Endres Cornelia , Hoefflin Rouven , Andrieux Geoffroy , Zwick Melissa , Karantzelis Nikolaos , Staehle Hans F. , Vinnakota Janaki Manoja , Duquesne Sandra , Mozaffari Jovein Miriam , Pfeifer Dietmar , Becker Heiko , Blazar Bruce R. , Zähringer Alexander , Duyster Justus , Brummer Tilman , Boerries Melanie , Baumeister Julian , Shoumariyeh Khalid , Li Juan , Green Anthony R. , Heidel Florian H. , Tirosh Itay , Pahl Heike L. , Leimkühler Nils , Köhler Natalie , de Toledo Marcelo A.S. , Koschmieder Steffen , Zeiser Robert
Published: September 2024

Abstract
Increasing evidence supports the interplay between oncogenic mutations and immune escape mechanisms. Strategies to counteract the immune escape mediated by oncogenic signaling could provide improved therapeutic options for patients with various malignancies. As mutant calreticulin (CALR) is a common driver of myeloproliferative neoplasms (MPN), we analyzed the impact of oncogenic CALRdel52 on the bone marrow (BM) microenvironment in MPN. Single-cell RNA sequencing revealed that CALRdel52 led to the expansion of TGFβ1-producing erythroid progenitor cells and promoted the expansion of FoxP3+ regulatory T cells (Treg) in a murine MPN model. Treatment with an anti-TGFβ antibody improved mouse survival and increased the glycolytic activity in CD4+ and CD8+ T cells in vivo, whereas T-cell depletion abrogated the protective effects conferred by neutralizing TGFβ. TGFβ1 reduced perforin and TNFα production by T cells in vitro. TGFβ1 production by CALRdel52 cells was dependent on JAK1/2, PI3K, and ERK activity, which activated the transcription factor Sp1 to induce TGFβ1 expression. In four independent patient cohorts, TGFβ1 expression was increased in the BM of patients with MPN compared with healthy individuals, and the BM of patients with MPN contained a higher frequency of Treg compared with healthy individuals. Together, this study identified an ERK/Sp1/TGFβ1 axis in CALRdel52 MPNs as a mechanism of immunosuppression that can be targeted to elicit T-cell–mediated cytotoxicity.

Significance: Targeting the mutant calreticulin/TGFβ1 axis increases T-cell activity and glycolytic capacity, providing the rationale for conducting clinical trials on TGFβ antagonists as an immunotherapeutic strategy in patients with myeloproliferative neoplasms.
Data from Ionizable STING-Activating Nanoadjuvants Enhance Tumor Immunogenicity and Potentiate Immunotherapy Efficacy in Solid Tumors
Authors: Xian Shiyun , Chen Xiaona , Ren Sihang , Chen Xiaolong , Wang Hangxiang
Published: September 2024

Abstract
Therapeutic strategies that induce inflammatory responses in immunologically “cold” tumors have the potential to improve immunotherapeutic outcomes. Pharmacologically activating the stimulator of interferon gene (STING) pathway induces innate immunity, subsequently enhancing tumor immunogenicity. Here, we developed a nanoadjuvant with tumor-restricted pharmacology that rapidly activated STING and reshaped the tumor microenvironment. The non-nucleotide STING agonist MSA-2 was chemically engineered with a piperazine motif linked by a saturated hydrocarbon chain of varying lengths to produce ionizable prodrugs that were further developed into nanoadjuvants. Compared with state-of-the-art liposomes, the nanoadjuvant displayed prolonged retention in the circulation and improved intratumoral delivery. In the acidic tumor microenvironment, the nanoadjuvant underwent polyethylene glycol deshielding, enabling efficient extravasation and penetration into tumors. Concomitantly, the STING prodrug escaped from the endo/lysosome compartment to partition into the cytosol for spontaneous esterase-catalyzed drug activation. In mouse models of syngeneic and chemically induced colorectal cancers, nanoparticle treatment provoked robust STING-mediated antitumor immunity, shifting the tumor immune landscape from immunosuppressed to tumoricidal. Additionally, the nanoadjuvant demonstrated antitumor efficacy in triple-negative breast cancer, which was further enhanced by the addition of immune checkpoint inhibitors. Collectively, this study demonstrates the safety and immune-stimulating effects of a STING-activating nanoadjuvant, supporting the clinical evaluation of this STING immunotherapeutic alone and in combination with other immunotherapies.

Significance: STING-activating nanoadjuvants rationally engineered using an ionizable prodrug approach for systemic administration are well-tolerated and yield durable antitumor immune responses, providing a potential immunotherapeutic strategy to improve cancer treatment.
Supplementary Table 8 from Somatic mosaic chromosomal alterations and death of cardiovascular disease causes among cancer survivors
Authors: Sun Maxine , Cyr Marie-Christyne , Sandoval Johanna , Lemieux Perreault Louis-Philippe , Busque Lambert , Tardif Jean-Claude , Dubé Marie-Pierre
Published: September 2024

Supplementary Table 8: The effect of mosaic loss of X chromosome on death of cardiovascular disease causes, coronary artery disease causes, from cancer, and any cause of death
Supplementary Table 15 from Somatic mosaic chromosomal alterations and death of cardiovascular disease causes among cancer survivors
Authors: Sun Maxine , Cyr Marie-Christyne , Sandoval Johanna , Lemieux Perreault Louis-Philippe , Busque Lambert , Tardif Jean-Claude , Dubé Marie-Pierre
Published: September 2024

Supplementary Table 15: Cox regression analyses evaluating the effect of mosaic chromosomal alterations on the risk of any cause of death by cancer type
Supplemental Table 3 from Nitrated polycyclic aromatic hydrocarbon (nitro-PAH) signatures and somatic mutations in diesel exhaust-exposed bladder tumors
Authors: Gonzalez Nicole , Rao Nina , Dean Michael , Lee Donghyuk , Hurson Amber N. , Baris Dalsu , Schwenn Molly , Johnson Alison , Prokunina-Olsson Ludmila , Friesen Melissa C. , Zhu Bin , Rothman Nathaniel , Silverman Debra T. , Koutros Stella
Published: September 2024

Case-case associations between REC and TP53 mutation, NEBCS
Supplemental Table 1 from Nitrated polycyclic aromatic hydrocarbon (nitro-PAH) signatures and somatic mutations in diesel exhaust-exposed bladder tumors
Authors: Gonzalez Nicole , Rao Nina , Dean Michael , Lee Donghyuk , Hurson Amber N. , Baris Dalsu , Schwenn Molly , Johnson Alison , Prokunina-Olsson Ludmila , Friesen Melissa C. , Zhu Bin , Rothman Nathaniel , Silverman Debra T. , Koutros Stella
Published: September 2024

Genes on panel
Supplementary Figure 1 from The Impact of Improved Treatments on Survival of Adult US Leukemia Patients: 1990 - 2018
Authors: Howlader Nadia , Sharon Elad , Bhattacharya Manami , Ehrlich Lori A. , Richardson Nicholas C. , Gormley Nicole J. , de Claro R. Angelo , Wood Amy E. , Mariotto Angela B. , Cronin Kathleen A.
Published: September 2024

Supplementary Figure 1: Trends in Mortality by Leukemia Subtypes and Race Ethnicity. Total US 1992-2018. Results are shown for mortality trends for CML (panel A), ALL (panel B), and CLL (panel C), 1992-2018. For each panel, we show age-adjusted mortality rates by five mutually exclusive race-ethnicity categories: non-Hispanic White, non-Hispanic Black, non-Hispanic Asian Pacific Islander, non-Hispanic American Indian/Alaskan Natives, and Hispanic.
Supplementary Table S1 from The Association of Neighborhood Characteristics and Frailty in Childhood Cancer Survivors: A Report from the St. Jude Lifetime Cohort Study
Authors: Schwartz Lindsay F. , Dhaduk Rikeenkumar , Howell Carrie R. , Brinkman Tara M. , Ehrhardt Matthew J. , Delaney Angela , Srivastava Deo Kumar , Lanctot Jennifer Q. , Armstrong Gregory T. , Robison Leslie L. , Hudson Melissa M. , Ness Kirsten K. , Henderson Tara O.
Published: September 2024

Supplementary Table S1 shows the differences in frailty status breakdowns for the SJLIFE community control cohort versus our study participants (N=3806)
Supplementary Table S5 from Associations of post-diagnosis lifestyle with prognosis in women with invasive breast cancer
Authors: Troeschel Alyssa N. , Hartman Terryl J. , McCullough Lauren E. , Ergas Isaac J. , Collin Lindsay J. , Kwan Marilyn L. , Ambrosone Christine B. , Flanders W Dana , Bradshaw Patrick T. , Cespedes Feliciano Elizabeth M. , Roh Janise M. , Wang Ying , Valice Emily , Kushi Lawrence H.
Published: September 2024

Posterior Median Hazard Ratios and 95% Credible Intervals from Piecewise Exponential Proportional Hazards Model for All-Cause Mortality, Breast Cancer-Specific Mortality, and Breast Cancer Recurrence in the Pathways Study
Supplementary Table S2 from Associations of post-diagnosis lifestyle with prognosis in women with invasive breast cancer
Authors: Troeschel Alyssa N. , Hartman Terryl J. , McCullough Lauren E. , Ergas Isaac J. , Collin Lindsay J. , Kwan Marilyn L. , Ambrosone Christine B. , Flanders W Dana , Bradshaw Patrick T. , Cespedes Feliciano Elizabeth M. , Roh Janise M. , Wang Ying , Valice Emily , Kushi Lawrence H.
Published: September 2024

Hazard ratios and 95% confidence intervals for associations of each of the 9 components of the 2-year post-diagnosis lifestyle score with all-cause mortality.
Supplementary Figure S1 from Associations of post-diagnosis lifestyle with prognosis in women with invasive breast cancer
Authors: Troeschel Alyssa N. , Hartman Terryl J. , McCullough Lauren E. , Ergas Isaac J. , Collin Lindsay J. , Kwan Marilyn L. , Ambrosone Christine B. , Flanders W Dana , Bradshaw Patrick T. , Cespedes Feliciano Elizabeth M. , Roh Janise M. , Wang Ying , Valice Emily , Kushi Lawrence H.
Published: September 2024

Cumulative incidence of all-cause mortality, breast cancer-specific mortality, and breast cancer recurrence among women diagnosed with invasive breast cancer in the Pathways Study, according to tertiles of the 2-year post-diagnosis lifestyle score, 2006–2018
Supplementary Figure S1 from Tobacco Smoke is a Major Source of Aromatic Amine Exposure in U.S. Adults: 2013-2014 National Health and Nutrition Examination Survey (NHANES)
Authors: Seyler Tiffany , Mazumder Shrila , Ahamed Rayaj , Zhu Wanzhe , Blount Benjamin C. , Apelberg Benjamin J. , Wang Lanqing
Published: September 2024

Supplementary Figure S1. Chemical structures of five AAs. Analytes that were monitored for isomeric separation but not quantified are indicated with an asterisk.
Supplementary Table 2 from Updated Review of Major Cancer Risk Factors and Screening Test Use in the United States, with a Focus on Changes During the COVID-19 Pandemic
Authors: Star Jessica , Bandi Priti , Nargis Nigar , Islami Farhad , Yabroff K Robin , Minihan Adair K. , Smith Robert A. , Jemal Ahmedin
Published: September 2024

Obesity and smoking prevalence by state from 2019 to 2021.
Supplementary Table S4-S10 from Circulating Sex Hormone Levels and Risk of Gastrointestinal Cancer: Systematic Review and Meta-Analysis of Prospective Studies
Authors: Liu Zhiqiang , Zhang Yingfan , Lagergren Jesper , Li Shanshan , Li Jingru , Zhou Zhixian , Hu Zhijian , Xie Shao-Hua
Published: September 2024

Supplementary Table S4 shows associations with prediagnostic circulating sex hormones levels for esophageal cancer, Supplementary Table S5 for gastric cancer, Supplementary Table S6 for liver cancer, Supplementary Table S7 for pancreatic cancer, Supplementary Table S8 for colorectal cancer, Supplementary Table S9 for colon cancer, and Supplementary Table S10 shows associations for rectal cancer, all in subgroup analyses.
Supplementary Table S1 from Circulating Sex Hormone Levels and Risk of Gastrointestinal Cancer: Systematic Review and Meta-Analysis of Prospective Studies
Authors: Liu Zhiqiang , Zhang Yingfan , Lagergren Jesper , Li Shanshan , Li Jingru , Zhou Zhixian , Hu Zhijian , Xie Shao-Hua
Published: September 2024

Supplementary Table S1 shows characteristics of studies included in the meta-analysis.
Supplementary Materials and Methods from Circulating Sex Hormone Levels and Risk of Gastrointestinal Cancer: Systematic Review and Meta-Analysis of Prospective Studies
Authors: Liu Zhiqiang , Zhang Yingfan , Lagergren Jesper , Li Shanshan , Li Jingru , Zhou Zhixian , Hu Zhijian , Xie Shao-Hua
Published: September 2024

This supplementary materials and methods section shows the detailed literature search strategies.
Supplementary Figure S7 from Circulating Sex Hormone Levels and Risk of Gastrointestinal Cancer: Systematic Review and Meta-Analysis of Prospective Studies
Authors: Liu Zhiqiang , Zhang Yingfan , Lagergren Jesper , Li Shanshan , Li Jingru , Zhou Zhixian , Hu Zhijian , Xie Shao-Hua
Published: September 2024

Supplementary Figure S7 shows forest plots (1), sensitivity analysis (2) and funnel plots (3) of the associations between prediagnostic circulating sex hormone levels and rectal cancer risk.
Supplementary Figure S6 from Circulating Sex Hormone Levels and Risk of Gastrointestinal Cancer: Systematic Review and Meta-Analysis of Prospective Studies
Authors: Liu Zhiqiang , Zhang Yingfan , Lagergren Jesper , Li Shanshan , Li Jingru , Zhou Zhixian , Hu Zhijian , Xie Shao-Hua
Published: September 2024

Supplementary Figure S6 shows forest plots (1), sensitivity analysis (2) and funnel plots (3) of the associations between prediagnostic circulating sex hormone levels and colon cancer risk.
Supplementary Figure S5 from Circulating Sex Hormone Levels and Risk of Gastrointestinal Cancer: Systematic Review and Meta-Analysis of Prospective Studies
Authors: Liu Zhiqiang , Zhang Yingfan , Lagergren Jesper , Li Shanshan , Li Jingru , Zhou Zhixian , Hu Zhijian , Xie Shao-Hua
Published: September 2024

Supplementary Figure S5 shows forest plots (1), sensitivity analysis (2) and funnel plots (3) of the associations between prediagnostic circulating sex hormone levels and colorectal cancer risk.
Supplementary Figure S2 from Circulating Sex Hormone Levels and Risk of Gastrointestinal Cancer: Systematic Review and Meta-Analysis of Prospective Studies
Authors: Liu Zhiqiang , Zhang Yingfan , Lagergren Jesper , Li Shanshan , Li Jingru , Zhou Zhixian , Hu Zhijian , Xie Shao-Hua
Published: September 2024

Supplementary Figure S2 shows forest plots (1), sensitivity analysis (2) and funnel plots (3) of the associations between prediagnostic circulating sex hormone levels and gastric cancer risk.
Supplemental Table 1 from Estimated ovulatory years prior to menopause and postmenopausal endogenous hormone levels
Authors: Cramer Daniel W. , Vitonis Allison F. , Huang Tianyi , Shafrir Amy L. , Eliassen A Heather. , Barbieri Robert L. , Hankinson Susan E.
Published: September 2024

Supplemental Table 1: Adjusted geometric mean hormone levels by lifetime ovulatory years quartile among postmenopausal women not using hormone therapy at the time of blood draw in the Nurses' Health Study; excluding hysterectomized women whose age at menopause was n=1683
Table S5 from Incidence trends and survival in early-onset esophagogastric adenocarcinoma: A Swedish population-based cohort study
Authors: Radkiewicz Cecilia , Asplund Johannes , Lagergren Jesper
Published: September 2024

Sex distribution, numbers (n) and percentages (%) in early- (age 20-54 years) and later-onset (age 55-84 years) esophagogastric adenocarcinoma patients diagnosed in years 2007-2019.
Table S4 from Incidence trends and survival in early-onset esophagogastric adenocarcinoma: A Swedish population-based cohort study
Authors: Radkiewicz Cecilia , Asplund Johannes , Lagergren Jesper
Published: September 2024

5-year relative survival in early- (age 20-49 years) and later-onset (age 50-84 years) esophagogastric adenocarcinoma diagnosed in years 2007-2019 together with early-to-later-onset excess mortality rate ratios (EMRR) with 95% confidence intervals (CI).
Table S3 from Incidence trends and survival in early-onset esophagogastric adenocarcinoma: A Swedish population-based cohort study
Authors: Radkiewicz Cecilia , Asplund Johannes , Lagergren Jesper
Published: September 2024

Early- (20-49) and later-onset (50-99) esophagogastric adenocarcinoma age-standardized incidence rate per 100,000 person-years by calendar period and age-adjusted annual percentage change over 1993-2019, with 95% confidence intervals (CI).
Figure S1 from Incidence trends and survival in early-onset esophagogastric adenocarcinoma: A Swedish population-based cohort study
Authors: Radkiewicz Cecilia , Asplund Johannes , Lagergren Jesper
Published: September 2024

Early- (age 20-54 years) and later-onset (age 55-99 years) esophagogastric adenocarcinoma age-standardized incidence rate (ASIR) per 100,000 person-years in men (blue) and women (red), presented as mean ASIR by calendar period, empirical estimates, and modeled linear predictions over years 1993-2019.
Supplementary Table 9 from Hepatocellular Carcinoma Surveillance Among Individuals with Cirrhosis: Trends by Payer, Etiology and Calendar Year, from a Statewide, Multi-Payer Dataset, 2010-2018
Authors: Hsu Christine D. , Henderson Louise M. , Jackson Bradford E. , Baggett Christopher D. , Jonsson Funk Michele , Olshan Andrew F. , Gupta Parul , Barritt A Sidney. , Sanoff Hanna K. , Wheeler Stephanie B. , Moon Andrew M. , Lund Jennifer L.
Published: September 2024

Supplementary Table 9 includes two-year cumulative incidences for HCC surveillance overall and by insurance type, by calendar year of cirrhosis diagnosis (% and 95% confidence intervals).
Supplementary Table 17 from Hepatocellular Carcinoma Surveillance Among Individuals with Cirrhosis: Trends by Payer, Etiology and Calendar Year, from a Statewide, Multi-Payer Dataset, 2010-2018
Authors: Hsu Christine D. , Henderson Louise M. , Jackson Bradford E. , Baggett Christopher D. , Jonsson Funk Michele , Olshan Andrew F. , Gupta Parul , Barritt A Sidney. , Sanoff Hanna K. , Wheeler Stephanie B. , Moon Andrew M. , Lund Jennifer L.
Published: September 2024

Supplementary Table 17 includes two-year cumulative incidences by cirrhosis etiology and by insurance, without imputing deaths for individuals insured through private insurance (% and 95% confidence intervals) (% and 95% confidence intervals).
Supplementary Table 12 from Hepatocellular Carcinoma Surveillance Among Individuals with Cirrhosis: Trends by Payer, Etiology and Calendar Year, from a Statewide, Multi-Payer Dataset, 2010-2018
Authors: Hsu Christine D. , Henderson Louise M. , Jackson Bradford E. , Baggett Christopher D. , Jonsson Funk Michele , Olshan Andrew F. , Gupta Parul , Barritt A Sidney. , Sanoff Hanna K. , Wheeler Stephanie B. , Moon Andrew M. , Lund Jennifer L.
Published: September 2024

Supplementary Table 12 includes the one-year cumulative incidences for HCC surveillance overall and by insurance type, by calendar year of cirrhosis diagnosis, excluding individuals with decompensated cirrhosis (% and 95% confidence intervals).
Supplementary Table 11 from Hepatocellular Carcinoma Surveillance Among Individuals with Cirrhosis: Trends by Payer, Etiology and Calendar Year, from a Statewide, Multi-Payer Dataset, 2010-2018
Authors: Hsu Christine D. , Henderson Louise M. , Jackson Bradford E. , Baggett Christopher D. , Jonsson Funk Michele , Olshan Andrew F. , Gupta Parul , Barritt A Sidney. , Sanoff Hanna K. , Wheeler Stephanie B. , Moon Andrew M. , Lund Jennifer L.
Published: September 2024

Supplementary Table 11 includes the proportion of time covered measures for the entire cohort, by surveillance type and by payer.
Supplementary Materials and Methods from Development and Demonstration of Tobacco Treatment Measures for Cancer Registries:
Novel Metrics for Quality Improvement
Authors: Hutcheson Tresza D. , Metcalf Tim , Ellerbeck Edward F. , Sanderson Cox Lisa , Hu Jinxiang , Chen Xi , Richter Kimber P.
Published: September 2024

Coding Manual for Cancer Registry Registrars
Supplementary Table S1 from Dying to Find Out: The Cost of Time at the Dawn of the Multicancer Early Detection Era
Authors: Klein Eric A. , Madhavan Sarina , Beer Tomasz M. , Bettegowda Chetan , Liu Minetta C. , Hartman Anne-Renee , Hackshaw Allan
Published: September 2024

Cancer types detected incidentally by NIPT
Supplementary Table S4 from Associations of race and ethnicity with hepatocellular carcinoma, decompensation, and mortality in US Veterans with cirrhosis
Authors: VoPham Trang , Cravero Anne , Feld Lauren D. , Green Pamela , Feng Ziding , Berry Kristin , Kim Nicole J. , Vutien Philip , Mendoza Jason A. , Ioannou George N.
Published: September 2024

Supplementary Table S4. Competing risks proportional hazards regression for the associations between race/ethnicity and risk of HCC, decompensated cirrhosis, and death in patients with cirrhosis overall and by cirrhosis etiology
Supplementary Table 8 from Sleep Behaviors, Genetic Predispositions, and Risk of Esophageal Cancer
Authors: Wang Xiaoyan , Tian Ruiyi , Zong Xiaoyu , Jeon Myung Sik , Luo Jingqin , Colditz Graham A. , Wang Jean S. , Tsilidis Konstantinos K. , Ju Yo-El S. , Govindan Ramaswamy , Puri Varun , Cao Yin
Published: September 2024

Supplementary Table 8 shows the joint associations between composite sleep score and genetic risk with EAC risk
Supplementary Table 6 from Sleep Behaviors, Genetic Predispositions, and Risk of Esophageal Cancer
Authors: Wang Xiaoyan , Tian Ruiyi , Zong Xiaoyu , Jeon Myung Sik , Luo Jingqin , Colditz Graham A. , Wang Jean S. , Tsilidis Konstantinos K. , Ju Yo-El S. , Govindan Ramaswamy , Puri Varun , Cao Yin
Published: September 2024

Supplementary Table 6 shows the association between composite sleep score and EAC risk with deaths as competing events
Supplementary Table 1 from Sleep Behaviors, Genetic Predispositions, and Risk of Esophageal Cancer
Authors: Wang Xiaoyan , Tian Ruiyi , Zong Xiaoyu , Jeon Myung Sik , Luo Jingqin , Colditz Graham A. , Wang Jean S. , Tsilidis Konstantinos K. , Ju Yo-El S. , Govindan Ramaswamy , Puri Varun , Cao Yin
Published: September 2024

Supplementary Table 1 shows the associations between SNPs and EAC risk
Table S6 from Field synopsis of environmental and genetic risk factors of sporadic early-onset colorectal cancer and advanced adenoma
Authors: Zhang Rongqi , Boakye Daniel , Yang Nan , Zhou Xuan , Zhou Yajing , Jiang Fangyuan , Yu Lili , Wang Lijuan , Sun Jing , Yuan Shuai , Chen Jie , Hamilton Ashleigh C. , Coleman Helen G. , Larsson Susanna C. , Little Julian , Dunlop Malcolm G. , Giovannucci Edward L. , Theodoratou Evropi , Li Xue
Published: September 2024

Supplementary Table 6 shows the basic characteristics of EOCRC, LOCRC and healthy controls in UK Biobank.
Table S3 from Field synopsis of environmental and genetic risk factors of sporadic early-onset colorectal cancer and advanced adenoma
Authors: Zhang Rongqi , Boakye Daniel , Yang Nan , Zhou Xuan , Zhou Yajing , Jiang Fangyuan , Yu Lili , Wang Lijuan , Sun Jing , Yuan Shuai , Chen Jie , Hamilton Ashleigh C. , Coleman Helen G. , Larsson Susanna C. , Little Julian , Dunlop Malcolm G. , Giovannucci Edward L. , Theodoratou Evropi , Li Xue
Published: September 2024

Supplementary Table 3 shows the list of environmental risk factors and their associations with early-onset colorectal cancer (EOCRC).
Table S2 from Field synopsis of environmental and genetic risk factors of sporadic early-onset colorectal cancer and advanced adenoma
Authors: Zhang Rongqi , Boakye Daniel , Yang Nan , Zhou Xuan , Zhou Yajing , Jiang Fangyuan , Yu Lili , Wang Lijuan , Sun Jing , Yuan Shuai , Chen Jie , Hamilton Ashleigh C. , Coleman Helen G. , Larsson Susanna C. , Little Julian , Dunlop Malcolm G. , Giovannucci Edward L. , Theodoratou Evropi , Li Xue
Published: September 2024

Supplementary Table 2 shows the quality rating of the included studies.
Supplementary Table 2 from Folate intake and ovarian cancer risk among women with endometriosis: a case-control study from the Ovarian Cancer Association Consortium
Authors: Gersekowski Kate , Ibiebele Torukiri I. , Doherty Jennifer A. , Harris Holly R. , Goodman Marc T. , Terry Kathryn L. , Wu Anna H. , Bandera Elisa V. , Qin Bo , Ong Jue-Sheng , Tyrer Jonathan P. , Dixon-Suen Suzanne C. , Modugno Francesmary , Risch Harvey A. , Webb Penelope M.
Published: September 2024

Supplementary Table 2 shows the single nucleotide polymorphisms (SNPs) used as instruments for folate level in the Mendelian randomization analysis.
Supplementary Figure 2 from Folate intake and ovarian cancer risk among women with endometriosis: a case-control study from the Ovarian Cancer Association Consortium
Authors: Gersekowski Kate , Ibiebele Torukiri I. , Doherty Jennifer A. , Harris Holly R. , Goodman Marc T. , Terry Kathryn L. , Wu Anna H. , Bandera Elisa V. , Qin Bo , Ong Jue-Sheng , Tyrer Jonathan P. , Dixon-Suen Suzanne C. , Modugno Francesmary , Risch Harvey A. , Webb Penelope M.
Published: September 2024

Supplementary Figure 2 shows two forest plots depicting the association between (A) dietary folate intake and (B) supplemental folate intake and ovarian cancer for women with endometriosis, stratified by potential effect modifiers