tbuckley/cabot-search huggingface dataset:
HBV shows different levels of adaptation to HLA class I-associated selection pressure correlating with markers of replication
Authors: Tatjana Schwarz, Johannes Ptok, Maximilian Damagnez, Christopher Menne, Elahe Salimi Alizei, Julia Lang-Meli, Michelle Maas, Daniel Habermann, Daniel Hoffmann, Julian Schulze Zur Wiesch, Georg M Lauer, Helenie Kefalakes, Markus Cornberg, Anke R M Kraft, Smaranda Gliga, Hans H Bock, Peter A Horn, Mala K Maini, Robert Thimme, Heiner Wedemeyer, Jacob Nattermann, Falko M Heinemann, Tom Luedde, Christoph Neumann-Haefelin, Andreas Walker, Jörg Timm
Journal: Journal of Hepatology (2024)

Immune responses by CD8 T cells are essential for control of HBV replication. Although selection of escape mutations in CD8 T-cell epitopes has been previously described in HBV infection, its overall influence on HBV sequence diversity and correlation with markers of HBV replication remain unclear. Whole-genome sequencing was applied to HBV isolates from 532 patients with chronic HBV infection and high-resolution HLA class I genotyping. Using a Bayesian model (HAMdetector) for identification of HLA-associated mutational states (HAMs), the frequency and location of residues under CD8 T-cell selection pressure were determined and the levels of adaptation of individual isolates were quantified. Using previously published thresholds for the identification of HAMs, a total of 295 residues showed evidence of CD8 T-cell escape, the majority of which were located in previously unidentified epitopes. Interestingly, HAMs were highly enriched in the HBV core protein compared to all other proteins. When individual HBV isolates were compared, different levels of adaptation to HLA class I immune pressure were noted. The level of adaptation increased with patient age and correlated with markers of replication, with low levels of adaptation in HBeAg-positive infection. Furthermore, the levels of adaptation negatively correlated with HBV viral load and HBsAg levels, consistent with high levels of HLA class I-associated selection pressure in patients with low replication levels. HBV sequence diversity is shaped by HLA class I-associated selection pressure with the HBV core protein being a predominant target of selection. Importantly, different levels of adaptation to immune pressure were observed between HBV infection stages, which need to be considered in the context of T-cell-based therapies. The immune response mediated by CD8 T cells plays a critical role in controlling HBV infection and shows promise for therapeutic strategies aimed at achieving a functional cure. This study demonstrates that mutational escape within CD8 T-cell epitopes is common in HBV and represents a key factor in the failure of immune control. Notably, the HBV core protein emerges as the primary target of CD8 T-cell selection pressure. Additionally, the observed correlation between HBV adaptation levels and viral replication markers indicates that CD8 T-cell immunity may influence transitions between phases of chronic HBV infection.
UK guidelines for the investigation and management of eosinophilia in returning travellers and migrants
Authors: Clare Thakker, Clare Warrell, Jessica Barrett, Helen L Booth, Peter L Chiodini, Sylviane Defres, Jane Falconer, Nathan Jacobs, Jayne Jones, Jonathan Lambert, Clare Leong, Angela McBride, Elinor Moore, Tara Moshiri, Laura E Nabarro, Geraldine O'Hara, Neil Stone, Clare van Halsema, Anna M Checkley
Journal: Journal of Infection (2024)

Eosinophilia is a common finding in returning travellers, migrants and other travelling groups. In this setting, it often indicates an underlying helminth infection. Infections associated with eosinophilia are frequently either asymptomatic or associated with non-specific symptoms but some can cause severe disease. Here the British Infection Association guidelines group has comprehensively reviewed and updated the UK recommendations for the investigation and management of eosinophilia in returning travellers, migrants and other relevant groups, first published in 2010.1 Literature reviews have been undertaken to update the evidence on the prevalence and causes of eosinophilia in these groups and on the treatment of relevant pathogens and clinical conditions. Diagnostic tests available to UK-based clinicians are summarised. Changes made to the guidelines include updates in the sections on the investigation and empirical treatment of asymptomatic eosinophilia and on the treatment of trichuriasis, lymphatic filariasis, onchocerciasis, hookworm, fascioliasis and taeniasis. Pathogens which are rarely encountered in UK practice have been removed from the guidelines and others added, including an expanded section on fungal infection. A section on off-license and rarely used drugs has been included.
A Phase 2 study of acimtamig (AFM13) in patients with CD30-positive, relapsed or refractory peripheral T-cell lymphomas
Authors: Won Seog. Kim, Jake Shortt, Pier Luigi Zinzani, Natalia Mikhailova, Dejan Radeski, Vincent Ribrag, Eva Domingo Domenech, Ahmed Sawas, Karenza Alexis, Michael Emig, Riham Elbadri, Pallavi Hajela, Paulien Ravenstijn, Sheena Pinto, Linta Garcia, Andre Overesch, Kerstin Pietzko, Steven Horwitz
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Patients with relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) generally have poor prognoses and limited treatment options. This study evaluated the efficacy of a novel CD30/CD16A bispecific innate cell engager, acimtamig (AFM13), in patients with R/R PTCL. Patients and Methods: Patients included those with CD30 expression in ≥1% of tumor cells and who were R/R following ≥1 prior line of systemic therapy. Acimtamig (200 mg) was administered once weekly in 8-week cycles. The primary endpoint was the overall response rate by fluorodeoxyglucose-PET per independent review committee; secondary and exploratory endpoints included duration of response, safety, progression-free survival, and overall survival. Results: The overall response rate in 108 patients was 32.4% [95% confidence interval (CI), 23.7, 42.1] with a complete response rate of 10.2% (95% CI, 5.2, 17.5); the median duration of response was 2.3 months (95% CI, 1.9, 6.5). Patients with R/R angioimmunoblastic T-cell lymphoma exhibited the greatest number of responses [53.3% (95% CI, 34.3, 71.7)]. Responses were independent of CD30 expression level, prior brentuximab vedotin treatment, or steroid premedication. Acimtamig exhibited a tolerable safety profile; the most common treatment-related adverse events were infusion-related reactions in 27 patients (25.0%) and neutropenia in 11 patients (10.2%). No cases of cytokine release syndrome or acimtamig-related deaths were reported. Despite exhibiting promising clinical activity and tolerable safety in a heavily pretreated PTCL population, the study did not meet the criteria for the primary endpoint. Conclusions: The promising clinical efficacy observed warrants further investigation, and development of acimtamig for patients with R/R CD30+ lymphomas continues in combination with allogeneic NK cells.
Phase II Trial of Induction Chemotherapy for Advanced Sinonasal Squamous Cell Carcinoma
Authors: Kevin J. Contrera, Renata Ferrarotto, Brandon Gunn, Shirley Y. Su, Merrill S. Kies, Bonnie S. Glisson, Adam S. Garden, Dianna Roberts, Curtis Hanba, Camilla O. Hoff, Adel El-Naggar, Michelle D. Williams, Shaan M. Raza, Franco DeMonte, Melissa M. Chen, Mark S. Chambers, Ehab Y. Hanna
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Outcomes after primary surgery for advanced sinonasal squamous cell carcinoma (SCC) are poor. We tested whether induction chemotherapy (IC) can improve disease control or organ preservation. Patients and Methods: A phase II trial evaluated previously untreated patients with stage II-IV, M0 sinonasal SCC. Patients received IC with docetaxel, cisplatin, and fluorouracil, followed by chemoradiotherapy (CRT) for responders and surgery with adjuvant radiotherapy or CRT for non-responders. The primary endpoints were overall response rate (ORR) and locoregional control (LRC). Secondary endpoints included progression-free survival (PFS), overall survival (OS), organ preservation, and treatment toxicity. Results: Of the 31 patients enrolled between 2008 and 2020, 28 were evaluated for efficacy. Disease was T4a, T4b, and N+ in 57%, 21%, and 36% of patients, respectively. The ORR was 82.1%; 17.9% of patients had stable disease, and 0% had progressive disease. Grade 3 and 4 adverse events (AE) occurred in 54% and 18% of patients, respectively; there were no Grade 5 AEs. The 2-year LRC and PFS rates were 64.3% (95% CI 40.4-77.6) and 52.4% (95% CI 32.3-69.0), respectively. The median PFS was 25.8 months. The median OS was 47.4 months, with a 2-year OS rate of 69.4% (95% CI 44.9-80.4). No survival difference was observed between surgery versus CRT (hazard ratio 1.07, 95% CI 0.9-3.84). Of patients alive at 2 years, 63% achieved organ preservation, avoiding maxillectomy (38%), craniotomy (13%), or orbital exenteration (38%). Conclusions: IC and response-directed treatment achieved promising disease control and added organ preservation for patients with advanced sinonasal SCC.
Targeting T-cell costimulation to the surface of tumor cells
Authors: Iñaki Eguren-Santamaría, Miguel F. Sanmamed, Paula Molero-Glez, Jose Luis Perez-Gracia, Ignacio Melero
Journal: Clinical Cancer Research (2024)

Summary Bispecific agents targeting tumor-cell surface antigens and activating receptors on T lymphocytes are being developed for solid tumors. Effective and safe strategies depend on target specificity and at least relative tumor-tissue confinement of T-cell activation. Novel evidence suggests that constructs targeting HER2 on tumor cells with the aim of providing costimulation (signal 2) to T lymphocytes via cluster of differentiation 137 (4-1BB) are safe and can meaningfully invigorate antitumor responses in a proportion of patients. See related article by Piha-Paul et al., p. XX
Phase Ib clinical and pharmacodynamic study of the TIE2 kinase inhibitor rebastinib with paclitaxel or eribulin in HER2-negative metastatic breast cancer
Authors: Jesus D. Anampa, Daniel L. Flynn, Cynthia Leary, Sun Oh, Xiaonan Xue, Maja H. Oktay, John S. Condeelis, Joseph A. Sparano
Journal: Clinical Cancer Research (2024)

Breast cancer cells disseminate to distant sites via Tumor Microenvironment of Metastasis (TMEM) doorways. The TIE2 inhibitor rebastinib blocks TMEM doorway function in the PyMT mouse model of breast cancer. We aimed to assess the safety and pharmacodynamics of rebastinib plus paclitaxel or eribulin in patients with HER2-negative metastatic breast cancer (MBC).
Homoharringtonine Added to Venetoclax and Azacitidine Improves Outcome and Mitigates Genetic Impact in Relapsed/Refractory AML: A Multi-center Cohort Study
Authors: Guopan Yu, Yu Zhang, Sijian Yu, Zhao Yin, Guangyang Weng, Na Xu, Xin Du, Dongjun Lin, Jie Xiao, Zhiqiang Sun, Hongyu Zhang, Xinquan Liang, Ziwen Guo, Weihua Zhao, Min Dai, Zhiping Fan, Li Xuan, Hui Liu, Dan Xu, Jieyu Ye, Xuejie Jiang, Pengcheng Shi, Hua Jin, Qifa Liu
Journal: Clinical Cancer Research (2024)

We investigated whether homoharringtonine (HHT) added to venetoclax plus azacitidine (VA) could improve outcomes and counteract the negative effects of genetic patterns in patients with relapsed/refractory acute myeloid leukemia (RR-AML).
Boston Marathon athlete performance outcomes and intra-event medical encounter risk associated with low energy availability indicators
Authors: Kristin E Whitney, Alexandra F DeJong Lempke, Trent Stellingwerff, Louise M Burke, Bryan Holtzman, Aaron L Baggish, Pierre A D'Hemecourt, Sophia Dyer, Chris Troyanos, Kaya Adelzadeh, Grace H Saville, Ida A Heikura, Nicole Farnsworth, Laura Reece, Anthony C Hackney, Kathryn E Ackerman
Journal: British Journal of Sports Medicine (2024)

To determine the association between survey-based self-reported problematic low energy availability indicators (LEA-I) and race performance and intra-event medical encounters during the Boston Marathon.
Early Change in C-Reactive Protein and Venous Thromboembolism in Patients Treated With Immune Checkpoint Inhibitors
Authors: Florian Moik, Jakob M Riedl, Dominik Barth, Franziska Berton, Michael Fink, Cornelia Englisch, Christoph Hoeller, Thorsten Fuereder, Leyla Ay, Ingrid Pabinger, Erika Richtig, Nikolaus John, Sarah M Kostmann, Philipp J Jost, Armin Gerger, Angelika Terbuch, Matthias Preusser, Cihan Ay
Journal: JACC CardioOncology (2024)

Patients with cancer treated with immune-checkpoint inhibitors (ICIs) have a substantial risk of venous thromboembolism (VTE). The association between ICI-induced inflammation and hypercoagulability is unclear, and no biomarkers currently exist to stratify VTE risk. The authors sought to determine the association between the early changes in C-reactive protein (CRP) after ICI initiation and the risk of VTE. This retrospective cohort study included patients with cancer initiating ICI therapy from 2 academic cancer centers, serving as discovery and external validation cohorts. Patients were stratified based on CRP trajectories during the first 3 months of ICI treatment, with a CRP rise defined as a 2-fold increase from baseline. Patients were followed for VTE for the duration of ICI therapy, and competing risk and time-dependent analyses were used. A total of 822 patients were included. In the discovery cohort (n = 405), the cumulative VTE incidence in patients with a CRP rise (n = 159, 39.3%) was 19.9% (95% CI: 8.4%-34.8%), compared with 8.6% (3.1%-17.6%) in those without a CRP rise. After adjusting for key patient- and cancer-specific confounders, the subdistribution HR for VTE in patients with a CRP rise was 2.64 (95% CI: 1.06-6.62). This was confirmed in the external validation cohort (n = 417; subdistribution HR: 2.25; 95% CI: 1.03-4.94), with VTE incidences of 22.9% (95% CI: 9.7%-39.3%) in patients with a CRP rise and 10.8% (95% CI: 7.4%-15.1%) in those without. The association between CRP rise and VTE risk was confirmed in a time-dependent analysis and was consistent after adjusting for disease progression as a potential time-dependent confounder. Early CRP changes during ICI therapy are associated with an increased risk of VTE, suggesting a potential association between ICI-induced inflammation and hypercoagulability. CRP trajectories may serve as a biomarker for ICI-associated VTE.
Lutetium-177 DOTATATE Therapy and Cardiac Outcomes in Patients With Neuroendocrine Tumor and Cardiac Metastases
Authors: Isabel G Scalia, Mohamad Bassam Sonbol, Juan M Farina, Milagros Pereyra, Yuxiang Wang, Tanios S Bekaii-Saab, Ming Yang, Heidi M Connolly, Patricia A Pellikka, Joerg Herrmann, Thorvardur R Halfdanarson, Jason S Starr, Sushil Allen Luis, Reza Arsanjani, Chadi Ayoub
Journal: JACC CardioOncology (2024)
Ferroptotic Neutrophils Induce Immunosuppression and Chemoresistance in Breast Cancer
Authors: Wenfeng Zeng, Ruihua Zhang, Penghan Huang, Minxia Chen, Houying Chen, Xin Zeng, Jiang Liu, Jiahui Zhang, Di Huang, Liyan Lao
Journal: Cancer Research (2024)

Abstract Inducing ferroptosis in tumor cells is emerging as a strategy for treating malignancies that are refractory to traditional treatment modalities. However, the consequences of ferroptosis of immune cells in the tumor microenvironment (TME) need to be better understood in order to realize the potential of this approach. In this study, we discovered that neutrophils in chemoresistant breast cancer are highly sensitive to ferroptosis. Reduction of the acyltransferase MBOAT1 in chemoresistance-associated neutrophils induced phospholipid reprogramming, switching the preference from monounsaturated fatty acids to polyunsaturated fatty acids, which increased their susceptibility to ferroptosis. Ferroptotic neutrophils secreted PGE2, IDO and oxidized lipids that suppressed the proliferation and cytotoxicity of antitumor CD8+ T cells. Furthermore, neutrophil ferroptosis was closely related to a distinct subset of IL-1beta+CXCL3+CD4+ (Fer-CD4) T lymphocytes, which were enriched in chemoresistant tumors. Fer-CD4 T cells orchestrated neutrophil ferroptosis by modulating MBOAT1 expression via IL-1beta/IL-1R1/NF-kappaB signaling. Moreover, Fer-CD4 T cells secreted CXCL3, IL-8 and S100A9 to replenish the neutrophil pool in the TME. Ferroptotic neutrophils in turn fostered Fer-CD4 T cell differentiation. In spontaneous tumorigenesis mouse models, targeting IL-1beta+ CD4+ T cells or IL-1R1+ neutrophils broke the crosstalk, restraining neutrophil ferroptosis, enhancing antitumor immunity, and overcoming chemoresistance. Overall, these findings uncover the role of neutrophil ferroptosis in shaping the immune landscape and propose appealing targets for restoring immunosurveillance and chemosensitivity in breast cancer.
Conditional Activation of c-MYC in Distinct Catecholaminergic Cells Drives Development of Neuroblastoma or Somatostatinoma
Authors: Tingting Wang, Lingling Liu, Jie Fang, Hongjian Jin, Sivaraman Natarajan, Heather Sheppard, Meifen Lu, Gregory Turner, Thomas Confer, Melissa Johnson, Jeffrey Steinberg, Larry Ha, Nour Yadak, Richa Jain, David J. Picketts, Xiaotu Ma, Andrew Murphy, Andrew M. Davidoff, Evan S. Glazer, John Easton, Xiang Chen, Ruoning Wang, Jun Yang
Journal: Cancer Research (2024)

Abstract c-MYC is an important driver of high-risk neuroblastoma. A lack of c-MYC–driven genetically engineered mouse models (GEMM) has hampered the ability to better understand mechanisms of neuroblastoma oncogenesis and to develop effective therapies. Here, we showed that conditional c-MYC induction via Cre recombinase driven by a tyrosine hydroxylase (Th) promoter led to a preponderance of PDX1+ somatostatinoma, a type of pancreatic neuroendocrine tumor (PNET). However, c-MYC activation via an improved Cre recombinase driven by a dopamine β-hydroxylase (Dbh) promoter resulted in neuroblastoma development. The c-MYC murine neuroblastoma tumors recapitulated the pathologic and genetic features of human neuroblastoma and responded to anti-GD2 immunotherapy and DFMO, an FDA-approved inhibitor targeting the MYC transcriptional target ODC1. Thus, c-MYC overexpression results in different but related tumor types depending on the targeted cell. The GEMMs represent valuable tools for testing immunotherapies and targeted therapies for these diseases.
An Autophagy-Targeting Chimera Induces Degradation of Androgen Receptor Mutants and AR-v7 in Castration-Resistant Prostate Cancer
Authors: Tae Hyun Bae, Ki Woon Sung, Tri M. Pham, Abdo J. Najy, Alaleh Zamiri, Hyejeong Jang, Su Ran Mun, Seongho Kim, Ha Kyoung Kwon, Yeon Sung Son, Dongping Shi, Steven Kregel, Elisabeth I. Heath, Michael L. Cher, Yong Tae Kwon, Hyeong-Reh C. Kim
Journal: Cancer Research (2024)

Abstract Genetic alterations play a pivotal role in various human diseases, particularly cancer. The androgen receptor (AR) is a crucial transcription factor driving prostate cancer (PCa) progression across all stages. Current AR-targeting therapies utilize competitive AR antagonists or pathway suppressors. However, therapy resistance often emerges due to AR mutations and AR splice variants, such as AR-v7. To overcome this, we developed ATC-324, an AR degrader using the innovative protein degradation technology platform AUTOphagy-TArgeting Chimera (AUTOTAC). ATC-324 was designed to comprise enzalutamide, an AR inhibitor, as a target-binding ligand and YT 6-2, a ligand of the autophagy receptor p62/SQSTM1, as an autophagy-targeting ligand. ATC-324 induces the formation of the AR/p62 complex, leading to autophagy-lysosomal degradation of AR. Importantly, ATC-324 effectively degrades AR mutants frequently detected in PCa and co-degrades AR-v7 as a heterodimer with full-length AR. ATC-324 reduces nuclear AR levels and downregulates the target gene expression of AR and AR-v7, leading to cytotoxicity in AR-positive PCa cells. We also provide evidence of the therapeutic potential of ATC-324 in vivo as well as ex vivo bone organ culture. Moreover, ATC-324 remains potent in enzalutamide-resistant PCa cells. These results demonstrate the potential of the AUTOTAC platform to target previously considered undruggable proteins and overcome certain drug resistance mechanisms.
Mutant PP2A Induces IGFBP2 Secretion to Promote Development of High-Grade Uterine Cancer
Authors: Terrance J. Haanen, Sophie Boock, Catherine G. Callahan, Irene Peris, Kaitlin P. Zawacki, Brynne Raines, Charles A. Nino, Brian Tran, Alexis Harold, Gabrielle Hodges Onishi, Matthew Hinderman, Amanda Dowdican, Wei Huang, Derek J. Taylor, Sarah E. Taylor, Mark W. Jackson, Analisa DiFeo, Caitlin M. O'Connor, Goutham Narla
Journal: Cancer Research (2024)

Abstract Uterine serous carcinoma (USC) and uterine carcinosarcoma (UCS) tumors are uniquely aggressive, suggesting that the primary tumor is intrinsically equipped to disseminate and metastasize. Previous work identified mutational hotspots within PPP2R1A, which encodes the Aα scaffolding subunit of protein phosphatase 2A (PP2A), a heterotrimeric serine/threonine phosphatase. Two recurrent heterozygous PPP2R1A mutations, P179R and S256F, occur exclusively within high-grade subtypes of uterine cancer and can drive tumorigenesis and metastasis. Elucidation of the mechanisms by which PP2A-Aα mutants promote tumor development and progression could help identify therapeutic opportunities. Here, we showed that expression of these mutants in USC/UCS cell-lines enhanced tumor-initiating capacity, drove a hybrid epithelial-to-mesenchymal (EM) plasticity phenotype, and elevated secretion of the tumorigenic cytokine IGFBP2. Therapeutic targeting of the IGFBP2/IGF1R signaling axis using small molecules and genetic approaches resulted in marked tumor growth inhibition. Mechanistically, PP2A regulated IGFBP2 expression through the transcription factor, NF-κB, which harbors a B56 recognition motif. Collectively, these results identify a role for PP2A in regulating paracrine cancer cell signaling that can be targeted to block the initiation and metastasis of high-grade uterine cancer.
The circRNA cEMSY Induces Immunogenic Cell Death and Boosts Immunotherapy Efficacy in Lung Adenocarcinoma
Authors: Yijian Zhang, Xuming Song, Yipeng Feng, Yuxian Qian, Bing Chen, Te Zhang, Hui Wang, Yuzhong Chen, Xinnian Yu, Hanlin Ding, Rutao Li, Pengfe Ge, Lin Xu, Gaochao Dong, Feng Jiang
Journal: Cancer Research (2024)

Abstract Immunogenic cell death (ICD) induces an active immune response. Activating ICD represents a potential approach to boost the anti-tumor activity of immunotherapy, highlighting the need to identify effective and safe ICD inducers. In this study, we identified a conserved, ICD-related circular RNA cEMSY by systematically screening ICD models induced by multiple cell stressors in lung adenocarcinoma (LUAD). cEMSY triggered ICD in LUAD both in vitro and in vivo, leading to the release of damage-associated molecular patterns and promoting T cell cross-priming by dendritic cells (DCs). Notably, the intratumoral delivery of lipid nanoparticle-encapsulated cEMSY induced a potent antitumor immune response in an immunosuppressed tumor model, which synergized with PD-1 blockade to facilitate long-term anti-tumor immunity with no apparent toxicities. Mechanistically, cEMSY mediated mitochondrial aggregation of the RNA-binding protein TDP-43 that enabled leakage of mitochondrial DNA to stimulate the cGAS–STING pathway, activating the antiviral immune response. Clinically, elevated expression of cEMSY correlated with enhanced infiltration of DCs and CD8+ T cells and favorable immunotherapy response in LUAD. Together, these findings support the dual potential of cEMSY as a target and biomarker for improving immune checkpoint inhibitor responses in LUAD.
A positive-feedback loop suppresses TNBC tumour growth by remodeling tumour immune microenvironment and inducing ferroptosis
Authors: Pingting Ye, Chunhui Wang, Yixuan Wen, Kang Fang, Qi Li, Xin Zhang, Jingxian Yang, Ruihao Li, Mengyao Chen, Xiaohan Tong, Shuo Shi, Chunyan Dong
Journal: Biomaterials (2024)