bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Dynamic intestinal stem cell plasticity and lineage remodeling by a nutritional environment relevant to human risk for tumorigenesis
Authors: Choi Jiahn , Zhang Xusheng , Li Wenge , Houston Michele , Peregrina Karina , Dubin Robert , Ye Kenny , Augenlicht Leonard
Published: September 2024

Abstract
NWD1, a purified diet establishing mouse exposure to key nutrients recapitulating levels that increase human risk for intestinal cancer, reproducibly causes mouse sporadic intestinal and colonic tumors reflecting human etiology, incidence, frequency and lag with developmental age. Complex NWD1 stem cell and lineage reprogramming was deconvolved by bulk and scRNAseq, scATACseq, functional genomics and imaging. NWD1 extensively, rapidly, and reversibly, reprogrammed Lgr5hi stem cells, epigenetically down-regulating Ppargc1a expression, altering mitochondrial structure and function. This suppressed Lgr5hi stem cell functions and developmental maturation of Lgr5hi cell progeny as cells progressed through progenitor cell compartments, recapitulated by Ppargc1a genetic inactivation in Lgr5hi cells in vivo. Mobilized Bmi1+, Ascl2hi cells adapted lineages to the nutritional environment and elevated antigen processing and presentation pathways, especially in mature enterocytes, causing chronic, pro-tumorigenic low-level inflammation. There were multiple parallels between NWD1 remodeling of stem cells and lineages with pathogenic mechanisms in human inflammatory bowel disease, also pro-tumorigenic. Moreover, the shift to alternate stem cells reflects that the balance between Lgr5 positive and negative stem cells in supporting human colon tumors is determined by environmental influences. Stem cell and lineage plasticity in response to nutrients supports historic concepts of homeostasis as a continual adaptation to environment, with the human mucosa likely in constant flux in response to changing nutrient exposures.
Implications: Although oncogenic mutations provide a competitive advantage to intestinal epithelial cells in clonal expansion, the competition is on a playing field dynamically sculpted by the nutritional environment, influencing which cells dominate in mucosal maintenance and tumorigenesis.
Data from A comparative study of neuroendocrine heterogeneity in small cell lung cancer and neuroblastoma
Authors: Cai Ling , DeBerardinis Ralph J. , Xie Yang , Minna John D. , Xiao Guanghua
Published: September 2024

Abstract
Lineage plasticity has long been documented in both small cell lung cancer (SCLC) and neuroblastoma (NBL), two clinically distinct neuroendocrine (NE) cancers. In this study, we quantified the NE features of cancer as NE scores and performed a systematic comparison of SCLC and NBL. We found NBL and SCLC cell lines have highly similar molecular profiles and shared therapeutic sensitivity. In addition, NE heterogeneity was observed at both the inter- and intra-cell line levels. Surprisingly, we did not find a significant association between NE scores and overall survival in SCLC or NBL. We described many shared and unique NE score-associated features between SCLC and NBL, including dysregulation of Myc oncogenes, alterations in protein expression, metabolism, drug resistance, and selective gene dependencies.

Implications: Our work establishes a reference for molecular changes and vulnerabilities associated with NE to non-NE transdifferentiation through mutual validation of SCLC and NBL samples.
Data from Mitochondrial uncoupling inhibits reductive carboxylation in cancer cells
Authors: Jiang Haowen , He Clifford Jiajun , Li Albert M. , He Bo , Li Yang , Zhou Meng-Ning , Ye Jiangbin
Published: September 2024

Abstract
When the electron transport chain (ETC) function is impaired, cancer cells rely on reductive carboxylation (RC) to convert α-ketoglutarate (αKG) to citrate for macromolecular synthesis, thereby promoting tumor growth. Currently, there is no viable therapy to inhibit RC for cancer treatment. In this study, we demonstrate that the mitochondrial uncoupler treatment effectively inhibits RC in cancer cells. Mitochondrial uncoupler treatment activates the ETC and increases the NAD+/NADH ratio. Using U-13C-glutamine and 1-13C-glutamine tracers, we show that mitochondrial uncoupling accelerates the oxidative TCA cycle and blocks RC under hypoxia, in von Hippel-Lindau (VHL) tumor suppressor-deficient kidney cancer cells, or under anchorage-independent growth condition. Together, these data demonstrate that mitochondrial uncoupling redirects α-KG from RC back to the oxidative TCA cycle, highlighting that the NAD+/NADH ratio is one key switch that determines the metabolic fate of α-KG. Inhibiting RC could be a key mechanism by which mitochondrial uncouplers inhibit tumor growth.
Data from A Novel Role of Prostate-Specific Membrane Antigen in Telomere Stability in Prostate Cancer Cells
Authors: Reddy Vidyavathi , Hwang Clara , Reddy G. Prem-Veer , Kim Sahn-Ho
Published: September 2024

Abstract
Prostate-specific membrane antigen (PSMA) expression increases with prostate cancer (PCa) grade and progression; however, the role of PSMA in PCa progression remains poorly understood. Telomere stability is essential for the survival and genome stability of cancer cells. We found massive telomere DNA damage in PSMA-negative PCa cells (PC-3 and DU145) compared to PSMA-positive PCa (LNCaP) cells. The ectopic expression of PSMA suppressed telomere DNA damage in PC3 cells. PSMA inhibitor, 2-PMPA, and PSMA knockdown induced telomere DNA damage in PSMA-positive LNCaP cells but not in PSMA-negative PC-3 cells, suggesting that PSMA plays a critical role in telomere stability in PCa cells. In addition, we observed that inhibition of PSMA or inhibition of glutamate receptor, which mediates PSMA-dependent activation of AKT, suppressed AKT phosphorylation and caused telomere DNA damage. Furthermore, 2-PMPA-induced telomere DNA damage in LNCaP cells was associated with telomere aberrations, such as telomere-telomere fusions, sister-chromatid telomere fusions, and telomere breakages. AKT is reported to promote cell growth by stabilizing telomere association with telomere-binding proteins TRF1 and TPP1. We observed that TRF1 and TPP1 transfection of LNCaP cells attenuated the inhibitory effect of 2-PMPA on cell growth and telomere DNA damage. Together, these observations indicate that PSMA role in maintaining telomere stability in PCa cells is mediated by AKT. Thus, these studies reveal an important role of PSMA in maintaining telomere stability that can promote cell survival and, thereby, PCa progression.
Implications: the role of PSMA in telomere stability suggests a strong correlation between PSMA expression and prostate cancer progression.
Data from USP1 expression driven by EWS::FLI1 transcription factor stabilizes Survivin and mitigates replication stress in Ewing sarcoma
Authors: Mallard Halle J. , Wan Shibiao , Nidhi Prakriti , Hanscom-Trofy Yvan D. , Mohapatra Bhopal , Woods Nicholas T. , Lopez-Guerrero Jose Antonio , Llombart-Bosch Antonio , Machado Isidro , Scotlandi Katia , Kreiling Natasha F. , Perry Megan C. , Mirza Sameer , Coulter Donald W. , Band Vimla , Band Hamid , Ghosal Gargi
Published: September 2024

Abstract
In this study, we identify USP1 as a transcriptional target of EWS::FLI1 and demonstrate the requisite function of USP1 in Ewing sarcoma (EWS) cell survival in response to endogenous replication stress. EWS::FLI1 oncogenic transcription factor drives most Ewing sarcomas, a pediatric bone cancer. EWS cells display elevated levels of R-loops and replication stress. The mechanism by which EWS cells override activation of apoptosis or cellular senescence in response to increased replication stress is not known. We show that USP1 is overexpressed in EWS and EWS::FLI1 regulates USP1 transcript levels. USP1 knockdown or inhibition arrests EWS cell growth and induces cell death by apoptosis. Mechanistically, USP1 regulates Survivin (BIRC5/API4) protein stability and the activation of caspase-9 and caspase-3/7 in response to endogenous replication stress. Notably, USP1 inhibition sensitizes cells to doxorubicin and etoposide treatment. Together, our study demonstrates that USP1 is regulated by EWS::FLI1, the USP1-Survivin axis promotes EWS cell survival, and USP1 inhibition sensitizes cells to standard of care chemotherapy.

Implications: High USP1 and replication stress levels driven by EWS::FLI1 transcription factor in Ewing sarcoma are vulnerabilities that can be exploited to improve existing treatment avenues and overcome drug resistance.
Data from Exon junction complex mediates the cap-independent translation of circular RNA
Authors: Lin Hui-Hsuan , Chang Chiu-Yuan , Huang Yi-Ren , Shen Che-Hung , Wu Yu-Chen , Chang Kai-Li , Lee Yueh-Chun , Lin Ya-Chi , Ting Wen-Chien , Chien Han-Ju , Zheng Yi-Feng , Lai Chien-Chen , Hsiao Kuei-Yang
Published: September 2024

Abstract
Evidence that circular RNAs (circRNAs) serve as protein template is accumulating. However, how the cap-independent translation is controlled remains largely uncharacterized. Here we show that the presence of intron and thus splicing promote cap-independent translation. By acquiring the exon junction complex (EJC) after splicing, the interaction between circRNA and ribosomes was promoted, thereby facilitating translation. Prevention of splicing by treatment with spliceosome inhibitor or mutating splicing signal hindered cap-independent translation of circRNA. Moreover, EJC-tethering using Cas13 technology reconstituted EJC-dependent circRNA translation. Finally, the level of a coding circRNA from succinate dehydrogenase assembly factor 2 (circSDHAF2) was found to be elevated in the tumorous tissues from patients with colorectal cancer (CRC) and shown to be critical in tumorigenesis of CRC in both cell and murine models. These findings reveal that EJC-dependent control of circSDHAF2 translation is involved in the regulation of oncogenic pathways.
Implications: EJC-mediated cap-independent translation of circRNA is implicated in the tumorigenesis of colorectal cancer.
Supplementary Table S5 from Validation of an abridged breast cancer risk prediction model for the general population
Authors: Spaeth Erika L. , Dite Gillian S. , Hopper John L. , Allman Richard
Published: September 2024

Supplementary Table S5 shows the five-year vs full-lifetime risk classification for 313-SNP BRISK for unaffected and affected women
Supplemental Table 1 from Risk Factors for Early Onset Sporadic Colorectal Cancer in Male Veterans
Authors: Imperiale Thomas F. , Myers Laura J. , Barker Barry C. , Larson Jason , Stump Timothy E. , Daggy Joanne K.
Published: September 2024

Supplemental Table 1: Contains descriptive data for all candidate variables in cases and controls
Supplementary Figures from Single-cell RNA sequencing unifies developmental programs of Esophageal and Gastric Intestinal Metaplasia.
Authors: Nowicki-Osuch Karol , Zhuang Lizhe , Cheung Tik Shing , Black Emily L. , Masque-Soler Neus , Devonshire Ginny , Redmond Aisling M. , Freeman Adam , di Pietro Massimilliano , Pilonis Nastazja , Januszewicz Wladyslaw , O'Donovan Maria , Tavare Simon , Shields Jacqueline D. , Fitzgerald Rebecca C.
Published: September 2024

This file captions for supplementary tables and supplementary figures S1-S28 together with their legends
Figure S5 from Distinct assemblies of heterodimeric cytokine receptors govern stemness programs in leukemia
Authors: Kan Winnie L. , Dhagat Urmi , Kaufmann Kerstin B. , Hercus Timothy R. , Nero Tracy L. , Zeng Andy GX. , Toubia John , Barry Emma F. , Broughton Sophie E. , Gomez Guillermo A. , Benard Brooks A. , Dottore Mara , Cheung Tung Shing Karen S. , Boutzen Helena , Samaraweera Saumya E. , Simpson Kaylene J. , Jin Liqing , Goodall Gregory J. , Begley C. Glenn , Thomas Daniel , Ekert Paul G. , Tvorogov Denis , D'Andrea Richard J. , Dick John E. , Parker Michael W. , Lopez Angel F.
Published: September 2024

Enrichment of the IL-3R hexamer versus dodecamer gene signature in primitive normal and leukemic stem cells.
Figure S3 from Distinct assemblies of heterodimeric cytokine receptors govern stemness programs in leukemia
Authors: Kan Winnie L. , Dhagat Urmi , Kaufmann Kerstin B. , Hercus Timothy R. , Nero Tracy L. , Zeng Andy GX. , Toubia John , Barry Emma F. , Broughton Sophie E. , Gomez Guillermo A. , Benard Brooks A. , Dottore Mara , Cheung Tung Shing Karen S. , Boutzen Helena , Samaraweera Saumya E. , Simpson Kaylene J. , Jin Liqing , Goodall Gregory J. , Begley C. Glenn , Thomas Daniel , Ekert Paul G. , Tvorogov Denis , D'Andrea Richard J. , Dick John E. , Parker Michael W. , Lopez Angel F.
Published: September 2024

IL3Rα P248 at the IL-3R assembly interface is critical for cell differentiation.
Supplementary Video S8 from Dynamic glycoprotein hyposialylation promotes chemotherapy evasion and metastatic seeding of quiescent circulating tumor cell clusters in breast cancer
Authors: Dashzeveg Nurmaa K. , Jia Yuzhi , Zhang Youbin , Gerratana Lorenzo , Patel Priyam , Shajahan Asif , Dandar Tsogbadrakh , Ramos Erika K. , Almubarak Hannah F. , Adorno-Cruz Valery , Taftaf Rokana , Schuster Emma J. , Scholten David , Sokolowski Michael T. , Reduzzi Carolina , El-Shennawy Lamiaa , Hoffmann Andrew D. , Manai Maroua , Zhang Qiang , D'Amico Paolo , Azadi Parastoo , Colley Karen J. , Platanias Leonidas C. , Shah Ami N. , Gradishar William J. , Cristofanilli Massimo , Muller William A. , Cobb Brian A. , Liu Huiping
Published: September 2024

Supplementary Video S8 shows the clustering video of scrRNA transfected ST6KO cells presented in Fig.5E.
Supplementary Video S6 from Dynamic glycoprotein hyposialylation promotes chemotherapy evasion and metastatic seeding of quiescent circulating tumor cell clusters in breast cancer
Authors: Dashzeveg Nurmaa K. , Jia Yuzhi , Zhang Youbin , Gerratana Lorenzo , Patel Priyam , Shajahan Asif , Dandar Tsogbadrakh , Ramos Erika K. , Almubarak Hannah F. , Adorno-Cruz Valery , Taftaf Rokana , Schuster Emma J. , Scholten David , Sokolowski Michael T. , Reduzzi Carolina , El-Shennawy Lamiaa , Hoffmann Andrew D. , Manai Maroua , Zhang Qiang , D'Amico Paolo , Azadi Parastoo , Colley Karen J. , Platanias Leonidas C. , Shah Ami N. , Gradishar William J. , Cristofanilli Massimo , Muller William A. , Cobb Brian A. , Liu Huiping
Published: September 2024

Supplementary Video S6 shows the clustering video of PAX treated cells presented in Fig.2E.
Supplementary Video S20 from Dynamic glycoprotein hyposialylation promotes chemotherapy evasion and metastatic seeding of quiescent circulating tumor cell clusters in breast cancer
Authors: Dashzeveg Nurmaa K. , Jia Yuzhi , Zhang Youbin , Gerratana Lorenzo , Patel Priyam , Shajahan Asif , Dandar Tsogbadrakh , Ramos Erika K. , Almubarak Hannah F. , Adorno-Cruz Valery , Taftaf Rokana , Schuster Emma J. , Scholten David , Sokolowski Michael T. , Reduzzi Carolina , El-Shennawy Lamiaa , Hoffmann Andrew D. , Manai Maroua , Zhang Qiang , D'Amico Paolo , Azadi Parastoo , Colley Karen J. , Platanias Leonidas C. , Shah Ami N. , Gradishar William J. , Cristofanilli Massimo , Muller William A. , Cobb Brian A. , Liu Huiping
Published: September 2024

Supplementary Video S20 shows the clustering video of siPODXL transfected ST6WT cells presented in Supplementary Fig.S14B.
Supplementary Video S10 from Dynamic glycoprotein hyposialylation promotes chemotherapy evasion and metastatic seeding of quiescent circulating tumor cell clusters in breast cancer
Authors: Dashzeveg Nurmaa K. , Jia Yuzhi , Zhang Youbin , Gerratana Lorenzo , Patel Priyam , Shajahan Asif , Dandar Tsogbadrakh , Ramos Erika K. , Almubarak Hannah F. , Adorno-Cruz Valery , Taftaf Rokana , Schuster Emma J. , Scholten David , Sokolowski Michael T. , Reduzzi Carolina , El-Shennawy Lamiaa , Hoffmann Andrew D. , Manai Maroua , Zhang Qiang , D'Amico Paolo , Azadi Parastoo , Colley Karen J. , Platanias Leonidas C. , Shah Ami N. , Gradishar William J. , Cristofanilli Massimo , Muller William A. , Cobb Brian A. , Liu Huiping
Published: September 2024

Supplementary Video S10 shows the clustering video of siCD97 transfected ST6KO cells presented in Fig.5E.
Table S19 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of The Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Sans Marta , Makino Yuki , Min Jimin , Rajapakshe Kimal I. , Yip-Schneider Michele , Schmidt C. Max , Hurd Mark W. , Burks Jared K. , Gomez Javier A. , Thege Fredrik I. , Fahrmann Johannes F. , Wolff Robert A. , Kim Michael P. , Guerrero Paola A. , Maitra Anirban
Published: September 2024

Differentially expressed genes between NKX6-2 overexpressing and control Kras;Gnas cell line.
Data from Integrative pan-cancer genomic and transcriptomic analyses of refractory metastatic cancer
Authors: Pradat Yoann , Viot Julien , Yurchenko Andrey A. , Gunbin Konstantin , Cerbone Luigi , Deloger Marc , Grisay Guillaume , Verlingue Loic , Scott Veronique , Padioleau Ismael , Panunzi Leonardo , Michiels Stefan , Hollebecque Antoine , Jules-Clement Gerome , Mezquita Laura , Laine Antoine , Loriot Yohann , Besse Benjamin , Friboulet Luc , Andre Fabrice , Cournede Paul-Henry , Gautheret Daniel , Nikolaev Sergey I.
Published: September 2024

Abstract
Metastatic relapse after treatment is the leading cause of cancer mortality, and known resistance mechanisms are missing for most treatments administered to patients. To bridge this gap, we analyze a pan-cancer cohort (META-PRISM) of 1,031 refractory metastatic tumors profiled via whole-exome and transcriptome sequencing. META-PRISM tumors, particularly prostate, bladder, and pancreatic types, displayed the most transformed genomes compared to primary untreated tumors. Standard-of-care resistance biomarkers were identified only in lung and colon cancers - 9.6% of META-PRISM tumors, indicating that too few resistance mechanisms have received clinical validation. In contrast, we verified the enrichment of multiple investigational and hypothetical resistance mechanisms in treated compared to non-treated patients, thereby confirming their putative role in treatment resistance. Additionally, we demonstrated that molecular markers improve six-month survival prediction, particularly in patients with advanced breast cancer. Our analysis establishes the utility of META-PRISM cohort for investigating resistance mechanisms and performing predictive analyses in cancer.
Data from Integrative analysis of a large real-world cohort of small cell lung cancer identifies distinct genetic subtypes and insights into histological transformation
Authors: Sivakumar Smruthy , Moore Jay A. , Montesion Meagan , Sharaf Radwa , Lin Douglas I. , Colon Caterina I. , Fleischmann Zoe , Ebot Ericka M. , Newberg Justin Y. , Mills Jennifer M. , Hegde Priti S. , Pan Quintin , Dowlati Afshin , Frampton Garrett M. , Sage Julien , Lovly Christine M.
Published: September 2024

Abstract
Small cell lung cancer (SCLC) is a recalcitrant neuroendocrine carcinoma with dismal survival outcomes. A major barrier in the field has been the relative paucity of human tumors studied. Here we provide an integrated analysis of 3,600 “real-world” SCLC cases. This large cohort allowed us to identify new recurrent alterations and genetic subtypes, including STK11-mutant tumors (1.7%) and TP53/RB1 wild-type tumors (5.5%), as well as rare cases that were human papillomavirus-positive. In our cohort, gene amplifications on 4q12 are associated with increased overall survival while CCNE1 amplification is associated with decreased overall survival. We also identify more frequent alterations in the PTEN pathway in brain metastases. Finally, profiling cases of SCLC containing oncogenic drivers typically associated with NSCLC demonstrates that SCLC transformation may occur across multiple distinct molecular cohorts of NSCLC. These novel and unsuspected genetic features of SCLC may help personalize treatment approaches for this fatal form of cancer.
Data from FH variant pathogenicity promotes purine salvage pathway dependence in kidney cancer
Authors: Wilde Blake R. , Chakraborty Nishma , Matulionis Nedas , Hernandez Stephanie , Ueno Daiki , Gee Michayla E. , Esplin Edward D. , Ouyang Karen , Nykamp Keith , Shuch Brian , Christofk Heather R.
Published: September 2024

Abstract
Fumarate accumulation due to loss of fumarate hydratase (FH) drives cellular transformation. Germline FH alterations lead to hereditary leiomyomatosis and renal cell cancer (HLRCC) where patients are predisposed to an aggressive form of kidney cancer. There is an unmet need to classify FH variants by cancer-associated risk. We quantified catalytic efficiencies of 74 variants of uncertain significance. Over half were enzymatically inactive which is strong evidence of pathogenicity. We next generated a panel of HLRCC cell lines expressing FH variants with a range of catalytic activities, then correlated fumarate levels with metabolic features. We found that fumarate accumulation blocks de novo purine biosynthesis, rendering FH-deficient cells reliant on purine salvage for proliferation. Genetic or pharmacologic inhibition of the purine salvage pathway reduced HLRCC tumor growth in vivo. These findings suggest pathogenicity of patient-associated FH variants and reveal purine salvage as a targetable vulnerability in FH-deficient tumors.
Supplemental Figures from mWTX-330, an IL 12 INDUKINE Molecule, Activates and Reshapes Tumor-infiltrating CD8+ T and NK Cells to Generate Antitumor Immunity
Authors: Nirschl Christopher J. , Brodkin Heather R. , Domonkos Celesztina , Dwyer Connor J. , Hicklin Daniel J. , Ismail Nesreen , Seidel-Dugan Cynthia , Steiner Philipp , Steuert Zoe , Sullivan Jenna M. , Winston William M. , Salmeron Andres
Published: September 2024

Supplemental Figures 1-10
Supplementary Table S2 from AXL inhibition improves the anti-tumor activity of chimeric antigen receptor T cells
Authors: Sakemura R. Leo , Hefazi Mehrdad , Cox Michelle J. , Siegler Elizabeth L. , Sinha Sutapa , Hansen Michael J. , Stewart Carli M. , Feigin Jennifer M. , Manriquez Roman Claudia , Schick Kendall J. , Can Ismail , Tapper Erin E. , Horvei Paulina , Adada Mohamad M. , Bezerra Evandro D. , Kankeu Fonkoua Lionel Aurelien. , Ruff Michael W. , Forsman Cynthia L. , Nevala Wendy K. , Boysen Justin C. , Tschumper Renee C. , Grand Cory L. , Kuchimanchi Kamesh R. , Mouritsen Lars , Foulks Jason M. , Warner Steven L. , Call Timothy G. , Parikh Sameer A. , Ding Wei , Kay Neil E. , Kenderian Saad S.
Published: September 2024

Supplementary Table S2
Supplementary Table S1 from Tumor-targeted non-ablative radiation promotes solid tumor CAR T-cell therapy efficacy
Authors: Quach Hue Tu. , Skovgard Matthew S. , Villena-Vargas Jonathan , Bellis Rebecca Y. , Chintala Navin K. , Amador-Molina Alfredo , Bai Yang , Banerjee Srijita , Saini Jasmeen , Xiong Yuquan , Vista William-Ray , Byun Alexander J. , De Biasi Andreas , Zeltsman Masha , Mayor Marissa , Morello Aurore , Mittal Vivek , Gomez Daniel R. , Rimner Andreas , Jones David R. , Adusumilli Prasad S.
Published: September 2024

List of antibodies and reagents used in this study
Data from Host Interactions with Engineered T-cell Micropharmacies
Authors: Bourne Christopher M. , Wallisch Patrick , Dacek Megan M. , Gardner Thomas J. , Pierre Stephanie , Vogt Kristen , Corless Broderick C. , Bah Mamadou A. , Romero-Pichardo Jesus E. , Charles Angel , Kurtz Keifer G. , Tan Derek S. , Scheinberg David A.
Published: September 2024

Abstract
Genetically engineered, cytotoxic, adoptively transferred T cells localize to antigen-positive cancer cells inside patients, but tumor heterogeneity and multiple immune escape mechanisms have prevented the eradication of most solid tumor types. More effective, multifunctional engineered T cells are in development to overcome the barriers to the treatment of solid tumors, but the interactions of these highly modified cells with the host are poorly understood. We previously engineered prodrug-activating enzymatic functions into chimeric-antigen receptor (CAR) T cells, endowing them with a killing mechanism orthogonal to conventional T-cell cytotoxicity. These drug-delivering cells, termed Synthetic Enzyme-Armed KillER (SEAKER) cells, demonstrated efficacy in mouse lymphoma xenograft models. However, the interactions of an immunocompromised xenograft with such complex engineered T cells are distinct from those in an immunocompetent host, precluding an understanding of how these physiologic processes may affect the therapy. Herein, we expanded the repertoire of SEAKER cells to target solid-tumor melanomas in syngeneic mouse models using specific targeting with TCR-engineered T cells. We demonstrate that SEAKER cells localized specifically to tumors, and activated bioactive prodrugs, despite host immune responses. We additionally show that TCR-engineered SEAKER cells were efficacious in immunocompetent hosts, demonstrating that the SEAKER platform is applicable to many adoptive cell therapies.
Data from AXL inhibition improves the anti-tumor activity of chimeric antigen receptor T cells
Authors: Sakemura R. Leo , Hefazi Mehrdad , Cox Michelle J. , Siegler Elizabeth L. , Sinha Sutapa , Hansen Michael J. , Stewart Carli M. , Feigin Jennifer M. , Manriquez Roman Claudia , Schick Kendall J. , Can Ismail , Tapper Erin E. , Horvei Paulina , Adada Mohamad M. , Bezerra Evandro D. , Kankeu Fonkoua Lionel Aurelien. , Ruff Michael W. , Forsman Cynthia L. , Nevala Wendy K. , Boysen Justin C. , Tschumper Renee C. , Grand Cory L. , Kuchimanchi Kamesh R. , Mouritsen Lars , Foulks Jason M. , Warner Steven L. , Call Timothy G. , Parikh Sameer A. , Ding Wei , Kay Neil E. , Kenderian Saad S.
Published: September 2024

Abstract
The receptor tyrosine kinase AXL is a member of the TAM (Tyro3, AXL, and proto-oncogene tyrosine-protein kinase Mer) family and plays pleiotropic roles in cancer progression. AXL is expressed in immunosuppressive cells, which contributes to decreased efficacy of immunotherapy. Therefore, we hypothesized that AXL inhibition could serve as a strategy to overcome resistance to chimeric antigen receptor T (CART)-cell therapy. To test this, we determined the impact of AXL inhibition on CD19-targeted CART (CART19)-cell functions. Our results demonstrate that T cells and CART cells express high levels of AXL. Specifically, higher levels of AXL on activated Th2 CART cells and M2-polarized macrophages were observed. AXL inhibition with small molecules or via genetic disruption in T cells demonstrated selective inhibition of Th2 CART cells, Th2 cytokines, reversal of CART-cell inhibition, and promotion of CART-cell effector functions. AXL inhibition is a novel strategy to enhance CART-cell functions through two independent, but complementary, mechanisms: targeting Th2 cells and reversing myeloid-induced CART-cell inhibition through selective targeting of M2-polarized macrophages.
Peripheral Blood–Derived PD-1/CD28–CD19 CAR–Modified PD-1+ T-Cell Therapy in Patients with Solid Tumors
Authors: Zhang Zhen , Zhao Xuan , Zhao Qitai , Chen Xinfeng , Li Congcong , Liu Yaqing , Shen Chunyi , Song Lijie , Miao Lijun , Guo Fuyou , Mou Xiaoning , Zhao Jie , Gu Weiyue , Zhang Yi
Published: September 2024

T cells expressing programmed cell death 1 (PD-1) in the peripheral blood (PB) of patients with tumors possess therapeutic potential; however, the immunosuppressive, PD-1–triggered signaling pathway and limited proliferative capacity of PD-1+ T cells present challenges to their therapeutic application. Here, we observed no discernible distinction between PD-1+ and PD-1− T cells in terms of clonal overlap. However, CD8+PD-1+ T cells from PB and tumor tissues exhibited tighter clustering based on clone size. Single-cell RNA sequencing analysis showed that PD-1+ T cells from PB highly expressed cytotoxicity-related genes and were enriched for T-cell activation–related pathways compared with PD-1− T cells from PB or tumor tissues. Consistent with this, PB-derived PD-1+ T cells exhibited strong cytotoxicity toward autologous tumor cells and tumor cell lines. To augment PD-1+ T-cell activity against solid tumors in vivo, we introduced a PD-1/CD28 fusion receptor combined with a CD19 chimeric antigen receptor into PD-1+ T cells, which were then expanded in vitro. The modified PD-1+ T cells exhibited superior proliferation and antitumor abilities in vitro. In addition, four patients with cancer were infused with autologous PD-1/CD28–CD19 chimeric antigen receptor PD-1+ T cells. None of these patients experienced severe side effects, and one patient with melanoma achieved a complete response that was maintained for 6.7 months. The three other patients had stable disease. Collectively, these results suggested that cell therapy with modified PB-derived PD-1+ T cells is both safe and effective, and it may constitute a promising treatment strategy for patients with cancer.
Supplementary Tables from Molecular evolution of classic Hodgkin lymphoma revealed through whole genome sequencing of Hodgkin and Reed Sternberg cells
Authors: Maura Francesco , Ziccheddu Bachisio , Xiang Jenny Z. , Bhinder Bhavneet , Rosiene Joel , Abascal Federico , Maclachlan Kylee H. , Eng Kenneth Wha. , Uppal Manik , He Feng , Zhang Wei , Gao Qi , Yellapantula Venkata D. , Trujillo-Alonso Vicenta , Park Sunita I. , Oberley Matthew J. , Ruckdeschel Elizabeth , Lim Megan S. , Wertheim Gerald B. , Barth Matthew J. , Horton Terzah M. , Derkach Andriy , Kovach Alexandra E. , Forlenza Christopher J. , Zhang Yanming , Landgren Ola , Moskowitz Craig H. , Cesarman Ethel , Imielinski Marcin , Elemento Olivier , Roshal Mikhail , Giulino-Roth Lisa
Published: September 2024

Supplementary Tables S1-S20
Supplementary Table S7 from In vivo screening unveils pervasive RNA-binding protein dependencies in leukemic stem cells and identifies ELAVL1 as a therapeutic target
Authors: Vujovic Ana , de Rooij Laura , Keyvani Chahi Ava , Chen He Tian , Yee Brian A. , Loganathan Sampath K. , Liu Lina , Chan Derek C. H. , Tajik Amanda , Tsao Emily , Moreira Steven , Joshi Pratik , Xu Joshua , Wong Nicholas , Balde Zaldy , Jahangiri Soheil , Zandi Sasan , Aigner Stefan , Dick John E. , Minden Mark D. , Schramek Daniel , Yeo Gene W. , Hope Kristin J.
Published: September 2024

Table S7 shows (a) reproducible peaks and (b) GO analysis of ELAVL1-bound transcripts identified in the eCLIP-sequencing data set. The negatively enriched (c) and positively-enriched (d) gene sets identified by GSEA of ELAVL1-bound and differentially expressed transcripts from the RN2c RNA-sequencing data set are shown.
Supplementary Table S4 from In vivo screening unveils pervasive RNA-binding protein dependencies in leukemic stem cells and identifies ELAVL1 as a therapeutic target
Authors: Vujovic Ana , de Rooij Laura , Keyvani Chahi Ava , Chen He Tian , Yee Brian A. , Loganathan Sampath K. , Liu Lina , Chan Derek C. H. , Tajik Amanda , Tsao Emily , Moreira Steven , Joshi Pratik , Xu Joshua , Wong Nicholas , Balde Zaldy , Jahangiri Soheil , Zandi Sasan , Aigner Stefan , Dick John E. , Minden Mark D. , Schramek Daniel , Yeo Gene W. , Hope Kristin J.
Published: September 2024

Table S4 shows limiting dilution analysis of secondary recipients transplanted with DMSO- or MS-444-treated bone marrow from primary mice
Data from A Phase Ib/II Study of Ivosidenib with Venetoclax ± Azacitidine in IDH1-Mutated Myeloid Malignancies
Authors: Lachowiez Curtis A. , Loghavi Sanam , Zeng Zhihong , Tanaka Tomoyuki , Kim Yi June , Uryu Hidetaka , Turkalj Sven , Jakobsen Niels Asger , Luskin Marlise R. , Duose Dzifa Y. , Tidwell Rebecca S.S. , Short Nicholas J. , Borthakur Gautam , Kadia Tapan M. , Masarova Lucia , Tippett George D. , Bose Prithviraj , Jabbour Elias J. , Ravandi Farhad , Daver Naval G. , Garcia-Manero Guillermo , Kantarjian Hagop , Garcia Jacqueline S. , Vyas Paresh , Takahashi Koichi , Konopleva Marina , DiNardo Courtney D.
Published: September 2024

Abstract
The safety and efficacy of combining the isocitrate dehydrogenase-1 (IDH1) inhibitor ivosidenib (IVO) with the BCL2 inhibitor venetoclax (VEN; IVO + VEN) ± azacitidine (AZA; IVO + VEN + AZA) were evaluated in four cohorts of patients with IDH1-mutated myeloid malignancies (n = 31). Most (91%) adverse events were grade 1 or 2. The maximal tolerated dose was not reached. Composite complete remission with IVO + VEN + AZA versus IVO + VEN was 90% versus 83%. Among measurable residual disease (MRD)–evaluable patients (N = 16), 63% attained MRD-­negative remissions; IDH1 mutation clearance occurred in 64% of patients receiving ≥5 treatment cycles (N = 14). Median event-free survival and overall survival were 36 [94% CI, 23–not reached (NR)] and 42 (95% CI, 42-NR) months. Patients with signaling gene mutations appeared to particularly benefit from the triplet regimen. Longitudinal single-cell proteogenomic analyses linked cooccurring mutations, antiapoptotic protein expression, and cell maturation to therapeutic sensitivity of IDH1-mutated clones. No IDH isoform switching or second-site IDH1 mutations were observed, indicating combination therapy may overcome established resistance pathways to single-agent IVO.
Significance:
IVO + VEN + AZA is safe and active in patients with IDH1-mutated myeloid malignancies. Combination therapy appears to overcome resistance mechanisms observed with single-agent IDH-inhibitor use, with high MRD-negative remission rates. Single-cell DNA ± protein and time-of-flight mass-cytometry analysis revealed complex resistance mechanisms at relapse, highlighting key pathways for future therapeutic intervention.

This article is highlighted in the In This Issue feature, p. 247
Promises and Pitfalls of Polycentric Federalism: The Case of Solar Power in India
Authors: Marquardt Jens , Dasgupta Shyamasree , Höhne Chris , Lederer Markus , Sankhyayan Pooja
Published: September 2024

Recognizing that no central authority can combat climate change, scholars have pointed to the potential of polycentric governance in tackling climate change. Yet, empirical evidence for such a claim is scarce, particularly in the Global South. This study analyzes the characteristics, promises, and pitfalls of polycentric governance to promote climate mitigation efforts in three Indian states. Our contribution is twofold: (1) conceptually, we propose a framework to investigate the promises and pitfalls of polycentric climate governance in a federalist system with a particular focus on aspects of scaling and institutionalization, and (2) empirically, we compare solar power development across three Indian states with favorable conditions for solar power but varying performance. Based on a qualitative analysis of interviews and documents, we show how state governments with different party backgrounds have been vital in implementing policy changes and overcoming political barriers. Still, very few bottom-up initiatives exist and were successfully institutionalized.
The Last Years of Polish Jewry
Authors: Leshchinsky Yankev
Published: September 2024

Ukrainian-born Yankev Leshchinsky (1876-1966) was the leading scholarly and journalistic analyst of Eastern European Jewish socioeconomic and political life from the 1920s to the 1950s. Known as “the dean of Jewish sociologists” and “the father of Jewish demography,” Leshchinsky published a series of insightful and moving essays in Yiddish on Polish Jewry between 1927 and 1937. Despite heightened interest in interwar Jewish communities in Poland in recent years, these essays (like most of Leshchinsky’s works) have never been translated into English.

The Last Years of Polish Jewry helps to rectify this situation by translating some of Leshchinsky’s key essays. A thoughtful Introduction by Robert Brym provides the context of the author’s life and work.

The essays in this volume, based on years of research and first-hand observation, focus on the period 1935-37. The rise of militant Polish nationalism and the ensuing anti-Jewish boycotts and pogroms; the increasing exclusion of Jews from government employment and the universities; the destitution, hunger, suicide, and efforts to emigrate that characterized Jewish life; the psychological toll taken by mass uncertainty and hopelessness—all this falls within the author’s ambit. Few works in English have the range and depth of Leshchinsky’s essays on the last years of the three million Polish Jews who were to perish at the hand of the Nazi regime.

This book will be of interest to researchers and students of Eastern European history and society, especially those with an interest in Eastern Europe’s Jewish communities on the brink of the Holocaust.
13. Jews flee Poland
Authors: Leshchinsky Yankev
Published: September 2024

Leshchinsky denies that he earlier claimed that all Polish Jews must emigrate. He did claim, and here repeats, that at least 50,000 to 60,000 Polish Jews must emigrate annually. These numbers are equal to annual natural increase plus 10,000 to 12,000 additional Jews. Their departure would make more than enough room for the 40,000 to 50,000 Jewish men and women who enter the paid labour force annually. Over the last fifteen years, up to 50,000 Polish, Romanian, and Lithuanian Jews migrated to South America. None returned, and many of them arranged for their family members to join them. They did not wait for the revolution, and the political struggle in Eastern Europe was not weakened by their departure. Nor was the struggle for equality in Poland weakened by the departure of more than 200,000 Jews to Palestine and North America. Between 300,000 and 350,000 Jews left Poland in the last fifteen years, easing the economic hardship of those who remained behind without influencing the intensity of the political struggle. Recently, 30,000 to 40,000 non-Jewish émigrés have returned to Poland annually with a bit of capital. However, no Jews have returned because they recognize how dire the situation is here for their people. Millions of Jews must and will remain in Poland and fight for full equality, but emigration is a medicine that will ease the patient’s condition, perhaps preventing the patient’s death. 25 July 1936.
Effectiveness of a digital lifestyle management intervention (levidex) to improve quality of life in people with multiple sclerosis: results of a randomized controlled trial
Authors: Meyer Björn , Betz Linda T. , Jacob Gitta A. , Krause Nicole , Riemann-Lorenz Karin , Gold Stefan M. , Pöttgen Jana , Heesen Christoph
Published: September 2024

Background

Multiple Sclerosis (MS) is a chronic inflammatory neurodegenerative disease with diverse symptomatology, significantly impacting patients’ quality of life (QoL). While pharmacological therapies focus primarily on reducing inflammation and relapse rates, non-pharmacological interventions, including digital health applications, have shown promise in improving QoL among persons with MS (PwMS). Pilot studies had shown the feasibility and acceptability of levidex, a digital health application based on cognitive behavioral therapy (CBT) principles, a broad set of behavior change techniques, and relevant lifestyle-change advice. This randomized controlled trial aimed to examine the effects of levidex on MS-related QoL over 6 months.

Methods

Participants who were diagnosed with MS for at least one year were recruited via the internet in Germany, using a secure survey software platform, and were randomly assigned to the intervention group (IG), in which they received standard care + levidex, or an active control group (CG), in which they received standard care and were offered web-adapted material on the topic of lifestyle change from the German Multiple Sclerosis Society (DMSG). The primary outcome was MS-related QoL after 6 months, measured by the Hamburg Quality of Life Questionnaire in MS (HAQUAMS); secondary outcomes included QoL subscales, sick days, and health behavior, among others. Analyses of Covariance (ANCOVA) were used to examine intervention effects at 6 months. Participants were recruited between November 2020 and February 2022.

Results

A total of 421 adult participants (mean age: 47.5, 78.1% women) were included and randomized (IG, n = 195, CG, n = 226). After 6 months, the IG exhibited significantly higher MS-related QoL, compared to the CG (total score HAQUAMS, adjusted group mean difference = -0.14, 95% CI: [-0.22, -0.06], p = 0.001; Cohen’s d = 0.23), with significant effects also observed on the cognitive and mood subscales. At 6 months, IG participants also reported significantly fewer sick days (median = 2 days in IG vs. 6 days in CG; W = 3939, p = 0.012) and significantly higher levels of daily activities, as measured by the Frenchay Activity Index, adjusted group mean difference = 1.37, 95% CI = [0.33, 2.40], p = 0.010; Cohen’s d = 0.16. Safety analyses showed no adverse events and good satisfaction.

Conclusions

Compared to the control group, levidex facilitated clinically relevant improvements in MS-related QoL, reduced sick days, and enhanced activity in PwMS over 6 months. These findings suggest that levidex can serve as an effective non-pharmacological adjunctive treatment element to standard care and could help improve QoL among PwMS.

Trial registration

Registered on 22.09.2020 at the German Clinical Trials Register DRKS00023023.
Investigating health risk behavior disparities in the United States with finite mixture modeling
Authors: Jaferian Sohrab , Farhadian Lian
Published: September 2024

Health disparities are ongoing challenges in the United States, with one of the underlying factors being the variation in health risk behaviors across different socioeconomic and demographic communities. In this cross-sectional ecological study, utilizing data from 26,781 US zip codes provided by the Centers for Disease Control and Prevention (CDC), we conducted generalized linear model regressions to explore the associations between race, poverty, education, and urban/rural status in areas. Our analysis indicated that areas with a higher prevalence of Black population and higher poverty levels are associated with a more significant number of unique health risk behaviors. Conversely, other racial groups were associated with fewer unique health risk behaviors, although they may still engage in higher levels of specific behaviors. These insights underscore the need for tailored public health strategies to address the disparities in health risk behaviors across different sub-populations. Additionally, we employed Finite Mixture Modeling (FMM) to identify distinct sub-populations in the United States based on health risk behaviors, specifically binge drinking, smoking, sleep deprivation, and physical inactivity, which are essential risk factors for chronic diseases such as cancer, diabetes, and cardiovascular diseases. We identified four clusters and conducted an in-depth analysis of the demographics and socioeconomic characteristics of the identified clusters. Our findings reveal that one cluster, characterized by the worst health risk behaviors, exhibited the highest poverty rate, the least favorable health insurance profile, and the lowest frequencies of post-secondary education attainment compared to the other three clusters. This cluster, therefore, warrants targeted public health interventions.
Establishment of in-house assay for screening of anti-SARS-CoV-2 protein inhibitors
Authors: Emam Merna H. , Mahmoud Mohamed I. , El-Guendy Nadia , Loutfy Samah A.
Published: September 2024

Developing a potent antiviral agent to combat Coronavirus Disease-19 (COVID-19) is of critical importance as we may be at risk of the emergence of new virus strains or another pandemic recurrence. The interaction between the SARS-CoV-2 spike protein and Angiotensin Converting Enzyme 2 (ACE2) is the main protein-protein interaction (PPI) implicated in the virus entry into the host cells. Spike-ACE2 PPI represents a major target for drug intervention. We have repurposed a previously described protein-protein interaction detection method to be utilized as a drug screening assay. The assay was standardized using Chitosan nanoparticles (CNPs) as the drug and SARS-CoV-2 spike-ACE2 interaction as the PPI model. The assay was then used to screen four natural bioactive compounds: Curcumin (Cur), Gallic acid (GA), Quercetin (Q), and Silymarin (Sil), and their cytotoxicity was evaluated in vitro. Production of the spike protein and the evaluation of its activity in comparison to a standard commercial protein was part of our work as well. Here we describe a novel simple immunofluorescent screening assay to identify potential SARS-CoV-2 inhibitors that could assess the inhibitory effect of any ligand against any PPI.

Graphical Abstract
Accurate determination of high sulfur content in sulfide samples: an optimized ICP-OES method
Authors: Zhang Lin , Yang Min , Wang Dong , Yu Kaixin , Chen Zhuoyun , Bing Xue , Zhao Peng , Bao Yiqing , Yin Xuebo
Published: September 2024

Determination of high sulfur content in sulfide minerals is crucial for various applications, including geochemistry, mining, and environmental monitoring. While inductively coupled plasma optical emission spectrometry (ICP-OES) is the preferred method for sulfur analysis, conventional sample preparation techniques often fall short when dealing with high sulfur concentrations. This study investigated optimized digestion conditions for accurate sulfur determination in sulfide minerals using ICP-OES. We employed anti-corrosion acid digestion bombs, an aqua regia–hydrofluoric acid system, and a digestion temperature of 180 °C, achieving exceptional results. Certified reference material recoveries ranged from 99.9 to 100.5%, with relative standard deviations between 0.42 and 0.84%. These results demonstrate the high accuracy and precision of the method. The optimized digestion protocol presented in this study provides a robust and reliable approach for accurate sulfur analysis in sulfide minerals, particularly for high concentrations.
Multidisciplinary team approach in management of anterior spinal dysraphism with unusual presentation: case series and surgical approach
Authors: Essa Abdelhakeem A. , Wadie Maximous Dawoud Doaa , Anwar Mohamed , Elkhayat Hussein , Taha Ismail
Published: September 2024

Objectives

To report our experience with three cases of anterior lumbosacral meningocele with our multidisciplinary team plan and perioperative management and surgical approach for each case.

Background

Anterior meningocele is a rare congenital form of spinal dysraphism that involves protrusion of the theca anteriorly into the retroperitoneal and presacral space through an anterior defect.

Method

Three cases with anterior meningocele at different spinal levels (lumbar and sacral) were operated at Neurosurgery Department at Assiut University hospital from June to November 2020 with multidisciplinary management plans that were tailored separately for each case.

Conclusion

Anterior meningocele is a rare form of spinal dysraphism and a challenging congenital anomaly that requires proper diagnosis and selection of surgical approach. Our case series outlines the importance of multidisciplinary team approach for tailoring perioperative management and surgical approach with intraoperative important steps.