tbuckley/cabot-search huggingface dataset:
Predicting adenine base editing efficiencies in different cellular contexts by deep learning
Authors: Lucas Kissling, Amina Mollaysa, Sharan Janjuha, Nicolas Mathis, Kim F Marquart, Yanik Weber, Woohyun J Moon, Paulo J C Lin, Steven H Y Fan, Hiromi Muramatsu, Máté Vadovics, Ahmed Allam, Norbert Pardi, Ying K Tam, Michael Krauthammer, Gerald Schwank
Journal: Genome biology (2025)

Abstract Background Adenine base editors (ABEs) enable the conversion of A•T to G•C base pairs. Since the sequence of the target locus influences base editing efficiency, efforts have been made to develop computational models that can predict base editing outcomes based on the targeted sequence. However, these models were trained on base editing datasets generated in cell lines and their predictive power for base editing in primary cells in vivo remains uncertain. Results In this study, we conduct base editing screens using SpRY-ABEmax and SpRY-ABE8e to target 2,195 pathogenic mutations with a total of 12,000 guide RNAs in cell lines and in the murine liver. We observe strong correlations between in vitro datasets generated by ABE-mRNA electroporation into HEK293T cells and in vivo datasets generated by adeno-associated virus (AAV)- or lipid nanoparticle (LNP)-mediated nucleoside-modified mRNA delivery (Spearman R = 0.83–0.92). We subsequently develop BEDICT2.0, a deep learning model that predicts adenine base editing efficiencies with high accuracy in cell lines ( R = 0.60–0.94) and in the liver ( R = 0.62–0.81). Conclusions In conclusion, our work confirms that adenine base editing holds considerable potential for correcting a large fraction of pathogenic mutations. We also provide BEDICT2.0 – a robust computational model that helps identify sgRNA-ABE combinations capable of achieving high on-target editing with minimal bystander effects in both in vitro and in vivo settings.
Determining the functional relationship between epigenetic and physical chromatin domains in Drosophila
Authors: Sandrine Denaud, Gonzalo Sabarís, Marco Di Stefano, Giorgio-Lucio Papadopoulos, Bernd Schuettengruber, Giacomo Cavalli
Journal: Genome biology (2025)

The tight correlation between topologically associating domains (TADs) and epigenetic domains in Drosophila suggests that the epigenome contributes to define TADs. However, it is still unknown whether histone modifications are essential for TAD formation and structure. By either deleting or shifting key regulatory elements needed to establish the epigenetic signature of Polycomb TADs, we show that the epigenome is not a major driving force for the establishment of TADs. On the other hand, physical domains have an important impact on the formation of epigenetic domains, as they can restrict the spreading of repressive histone marks and looping between cis-regulatory elements.
An echocardiographic prognostic risk stratification decision tree to determine adverse events in Anderson-Fabry disease
Authors: Luke Stefani, Anita Boyd, Jennifer Pham, Matthew Zada, Peter Emerson, Kerry Devine, Michel Tchan, Liza Thomas
Journal:  (2025)

Abstract Aims Anderson–Fabry disease (AFD) is an X-linked disease, with cardiac involvement resulting in increased left ventricular (LV) wall thickness. Speckle tracking echocardiography analysis may be more sensitive in the assessment of myocardial impairment in AFD patients and have prognostic value. Our aim was to evaluate LV and left atrial (LA) dysfunction by traditional and strain parameters in AFD patients and evaluate prognostic utility. Methods and results Fifty-six AFD patients were age- and sex-matched to 56 healthy controls. LV global longitudinal strain (GLS) and LA reservoir strain (LASR) were significantly lower in male (GLS: 19.38[3.21] vs. 17.8[7.0], P = 0.009; LASR: 38.07 ± 6.67 vs. 31.12 ± 6.76, P = 0.003) and female (GLS: 20.58 ± 1.63 vs. 19.29 ± 1.67, P = 0.003; LASR: 38.77 ± 7.43 vs. 33.13 ± 6.06, P &amp;lt; 0.001) AFD patients compared with controls. Reduced strain parameters were also seen in female AFD patients with normal wall thickness (GLS: 20.88 ± 1.74 vs. 19.72 ± 1.53, P = 0.037; LASR: 40.09 ± 7.15 vs. 34.79 ± 6.20, P = 0.004). 53/56 AFD patients had a median follow-up of 43[81] months; 11/53 experienced an adverse cardiovascular event (i.e. cardiac death, myocardial infarction, arrhythmias, stroke. and heart failure). LV wall thickness, LAVImax, and LV GLS displayed good sensitivity and specificity for adverse cardiac events. A prognostic risk decision tree comprising of these parameters demonstrated good predictive value for adverse events (AUC = 0.910). Conclusion We demonstrate differences in LV and LA echocardiographic parameters in AFD patients compared with healthy controls, including female AFD patients with normal LV wall thickness. A prognostic risk decision tree stratified AFD patients into three groups with the highest risk group demonstrating more AFD-related adverse events.
HGF/c‐Met Axis‐Targeted Nanotherapy via GSH‐Responsive Polymer Platforms Suppresses Uveal Melanoma Metastasis
Authors: Hui Tao, Hanhan Liu, Hanchen Zhang, Hong Ren, Binyu Wen, Jing Zhang, Jiaqi Du, Ziyi Cai, Zhihong Deng
Journal: Advanced Healthcare Materials (2025)

Abstract Uveal melanoma (UM), a malignant tumor originating within the ocular, characterizes high metastasis and lethality among patients. Cancer stem cells (CSCs) distinguished by the c‐Met protein are believed to mediate tumor metastasis in UM. However, the low bioavailability of c‐Met inhibitors like Crizotilib (Criz) limits their clinical application. Herein, a GSH‐responsive nanoparticle named NP @Oxa/Criz to precisely deliver Criz and Oxaliplatin (Oxa) is synthesized in this study. The dual‐action mechanism of NP @Oxa/Criz inhibits the HGF/c‐Met axis to prevent the nuclear translocation of β‐Catenin, thereby reducing the transcription of metastasis‐associated genes and undermining the stemness and metastasis of UM cells. Simultaneously, NP @Oxa/Criz induces immunogenic cell death to boost anti‐tumor immunity. In vivo studies demonstrate that NP @Oxa/Criz can accumulate in tumor sites, significantly eradicating the primary UM in the ocular and suppressing the metastasis UM in the liver and peritoneal. The outcomes from this work illuminate the therapeutic mechanisms of NP @Oxa/Criz and provide a precise and potent nanotherapeutic strategy for clinical treatment and research in highly metastatic UM.
Correspondence on ‘Characteristics of second primary malignancies following bispecific antibodies therapy’ by Liang<i>et al</i>
Authors: Yan Jin, Yongli Jin, Yan Cui, Rongzhen Zheng
Journal: Journal for ImmunoTherapy of Cancer (2025)

We commend Liang et al for shining a spotlight on second primary malignancies after bispecific antibody (BsAb) therapy, yet several clinical nuances deserve consideration. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS)-derived case-fatality rates likely overstate risk, prior genotoxic treatments confound causality, and pooling heterogeneous BsAb constructs may blur construct-specific signals. The 124-day median latency hints at misclassification, while sparse African data limit global relevance. Risk-adapted surveillance—grounded in clonal haematopoiesis, prior cytotoxic exposure and BsAb construct—may be more pragmatic than blanket monitoring.
Exploring molecular imaging to investigate immune checkpoint inhibitor-related toxicity
Authors: Eva Peeters, Evelien A J van Genugten, Sandra Heskamp, I Jolanda M de Vries, Carla van Herpen, Hans J P M Koenen, Manfred Kneilling, Rachel S van der Post, Willemijn A van Dop, Harm Westdorp, Erik Aarntzen
Journal: Journal for ImmunoTherapy of Cancer (2025)

Immune checkpoint inhibitors (ICI) boost the endogenous anticancer immunity, evoking long-lasting anticancer responses in a subset of patients with solid tumors. Simultaneously, ICI are also associated with serious toxicities, impacting treatment duration and the quality of life. The proposed processes underlying ICI-related toxicity include T-cell activation and recruitment to non-tumor tissues, involvement of other immune cells and fibroblasts and the host’ microbiome composition. However, the exact mechanisms of these processes remain incompletely understood, hindering clinicians’ ability to predict and identify ICI-related toxicity in the early stages of treatment. Molecular imaging may play a role as a non-invasive biomarker, providing a tool to study ICI-related toxicity. This review discusses the applications of molecular imaging to answer questions regarding the mechanisms, detection, and prediction of ICI-related toxicity. Potential targets and the current state of development of suitable imaging techniques are discussed.
Oncolytic viruses targeting CD47: a new road to success?
Authors: Chris H Takimoto, Michael J Wick
Journal: Journal for ImmunoTherapy of Cancer (2025)

Clinical success in the therapeutic targeting of the CD47 signaling pathway has thus far remained elusive despite a promising scientific rationale. Use of oncolytic viruses to deliver CD47 targeting agents represents a novel approach to modulate the immunological landscape of the tumor microenvironment and to generate a systemic antitumor immune response. In recent preclinical studies, an oncolytic herpes simplex virus-1 engineered to express an inhibitory CD47-binding nanobody demonstrated promising antitumor activity. Several other oncolytic viruses engineered to express CD47 inhibitory molecules are also in preclinical development. Oncolytic viruses have the potential to mitigate drug delivery issues and may avoid systemic toxicities that have limited conventional CD47 targeting therapeutics. These novel therapeutics warrant further evaluation in clinical trials. The potential advantages, limitations, and remaining critical questions regarding this strategic approach are discussed here.
Early dynamics of clinical and laboratory parameters predict primary refractory disease in patients with metastatic urothelial carcinoma receiving atezolizumab
Authors: Christopher J Graser, Thomas O McDonald, Paul J Catalano, Guru Sonpavde, Franziska Michor
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background In patients with metastatic urothelial carcinoma (mUC) receiving programmed cell death ligand 1 (PD-L1) inhibitors, it is critically important to identify primary refractory patients very early to enable modification of therapy before clinical progression and decline of performance status. We hypothesized that baseline and early-on-treatment (EOT) parameters may help identify patients likely to have primary refractory disease. Methods We considered baseline and EOT variables measured up to 5 weeks after initiating therapy in the phase 3 clinical trial IMvigor211, which compared atezolizumab versus chemotherapy, in muC patients who had progressed on platinum-based chemotherapy. We used least absolute shrinkage and selection operator-regularized logistic regression models to predict the risk of primary refractory disease employing clinical and laboratory variables. Results 902 patients were evaluable for analysis. Our baseline model achieves an area under the curve (AUC) of 0.730, 0.717 for the atezolizumab group and 0.696 for the chemotherapy group. The AUC increases to 0.848 overall with EOT parameters, 0.871 for the atezolizumab group and 0.788 for the chemotherapy group. The EOT model suggests that 33.7% of patients receiving atezolizumab may benefit from switching to chemotherapy, reducing their risk of primary refractoriness from 67.1% to 51.5%. Conclusions Our prediction model employs readily available and routinely measured clinical and laboratory factors, such as urine-specific gravity, presence of liver metastases, and total protein and erythrocyte counts. It robustly identifies patients with early primary refractory disease to atezolizumab before clinical progression and may inform therapeutic decisions. Validation in larger independent cohorts and other treatments is required.
Immune checkpoint inhibitor-associated risk for venous thromboembolism: a comprehensive analysis
Authors: Tamara A Sussman, Anita Giobbie-Hurder, Ian D Dryg, Michael Manos, Jason L Weirather, Nicole R LeBoeuf, F Stephen Hodi, Jean M Connors
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background The relationship between venous thromboembolism (VTE) and immune checkpoint inhibitor therapy (ICI) is unclear. This analysis investigates the incidence of and risk factors for VTE in VTE-naive patients with cancer receiving ICI treatment. Methods A retrospective cohort study of patients receiving any type or combination of ICI from 2009 to 2022 at Dana-Farber Cancer Institute was conducted to identify VTE occurring after initiation of ICI treatment. Cumulative incidences of VTE were determined using Fine and Gray’s methods. Associations between VTE, ICI regimens, and clinical risk factors were evaluated using propensity-score stratified, multivariable Cox proportional hazards models. Results In 10,638 patients without a prior history of VTE, the 6-month cumulative incidence of VTE was 7.6% (95% CI: 7.1% to 8.1%) and 11.1% (95% CI: 10.5% to 11.8%) at 12 months. Clinical risk factors included: age 15–59 (HR 1.27; 95% CI: 1.12 to 1.43; p=0.002), obesity (HR: 1.41; 95% CI: 1.16 to 1.71) , and history of anticoagulation prior to ICI start (HR: 1.43; 95% CI: 1.26 to 1.61). Compared with pembrolizumab, treatment with ipilimumab/nivolumab increased the risk of VTE (HR: 1.36; 95% CI: 1.02 to 1.82), while durvalumab conveyed lower risk (HR: 0.52; 95% CI: 0.31 to 0.87). Treatment with programmed cell death ligand 1 had significantly reduced risk of VTE (HR: 0.79; 95% CI: 0.63 to 0.99) compared with programmed cell death 1 monotherapy. Dual ICI blockade with cytotoxic T lymphocyte antigen 4/PD-1 significantly increased the risk of VTE (HR: 1.43; 95% CI 1.12 to 1.84). Initiation of anticoagulation after starting ICI for indications other than VTE reduced the risk by 40% (HR: 0.60, 95% CI: 0.48 to 0.73). Conclusions ICI treatment appears to be independently associated with a high incidence of VTE in patients with cancer warranting further investigation.
Blocking LIF and PD-L1 enhances the antitumor efficacy of SBRT in murine PDAC models
Authors: Jian Ye, Shuyang S Qin, Angela L Hughson, Gary Hannon, Noah A Salama, Tara G Vrooman, Maggie L Lesch, Sidney Lesser, Sarah L Eckl, Rachel Jewell, Lauren Benoodt, Bradley N Mills, Carl J Johnston, Edith Lord, Brian A Belt, Laura M Calvi, David Linehan, Nadia Luheshi, Jim Eyles, Scott A Gerber
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Recent preclinical and clinical data suggest that leukemia inhibitory factor (LIF) is a potential target for various tumor types including pancreatic ductal adenocarcinoma as LIF is involved in multiple protumor processes including cancer stem cell maintenance, epithelial–mesenchymal transition (EMT), immunosuppression, and chemo/radioresistance. Anti-LIF antibody therapy has demonstrated safety and tolerability but limited efficacy in phase 1 clinical trial in advanced solid tumors. This prompted us to explore combination therapies, suggesting that LIF blockade, when combined with standard-of-care chemotherapy, radiotherapy, and/or immunotherapy, could present a promising therapeutic strategy. Methods We evaluated the impact of combining systemic inhibition of LIF/programmed death-ligand 1 (PD-L1) with localized stereotactic body radiotherapy (SBRT) on tumor progression across multiple murine orthotopic pancreatic tumor models and examined systemic antitumor immunity using a hepatic rechallenge model. The antitumor immune response was characterized throughflow cytometry and Luminex assays. To identify differentially expressed genes and signaling pathways following treatment, we performed bulk RNA sequencing on pancreatic tumors. Additionally, single-cell RNA sequencing was conducted to further examine changes in tumor-infiltrating immune cells and their signaling pathways. Results We showed that simultaneous inhibition of LIF and PD-L1 significantly amplified the antitumor efficacy of SBRT, resulting in extended survival. The triple therapy (SBRT+anti-LIF+anti-PD-L1) generated an immunostimulatory tumor microenvironment, characterized by a proinflammatory shift in the cytokine/chemokine profile, increased infiltration of effector CD8 + T cells, and upregulated activation or maturation signals in tumor-infiltrating CD8 + T cells and macrophages. The beneficial effects of triple therapy were mostly abrogated by depletion of CD8 + T cells. In addition, triple therapy downregulated pathways related to tumor stemness, proliferation, and metabolism, and reduced EMT. Importantly, the combination of local SBRT treatment with systemic LIF and PD-L1 blockade resulted in long-term systemic antitumor memory.
PDZ domains of PATJ facilitate immunological synapse formation to promote T cell activation
Authors: Xinxin Xiong, Danyang Wang, Liping Xu, Siyu Chen, Jingjing He, Xiaomin Zhang, Ziqian Fang, Jianeng Zhang, Wende Li, Penghui Zhou
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background The highly organized structures of the immunological synapse (IS) are crucial for T cell activation. PDZ domains might be involved in the formation of the IS by serving as docking sites for protein interactions. In this study, we investigate the role of the PALS1-associated tight junction protein (PATJ), which contains 10 PDZ domains, in the formation of IS and its subsequent impact on T cell activation. Methods To elucidate the function of PATJ, we generated murine models with conditional T cell-specific knockout of Patj and assessed T cell activation both in vitro and in vivo within the context of infection and cancer. We employed confocal microscopy to visualize the formation of IS between T cells and antigen-presenting cells in the absence of Patj . A series of PATJ truncations containing different combinations of PDZ domains was used to identify the minimal domain required for effective T cell receptor signaling. The identified active PDZ domain was then incorporated into mesothelin (MSLN)-specific chimeric antigen receptor (CAR) to evaluate its impact on CAR-T cell cytotoxicity against solid tumors. Results We observed a rapid increase in PATJ expression during T cell activation. Conditional knockout of Patj in T cells showed impaired immunity against infection and cancer in murine models. Mechanistically, ablation of Patj impedes IS formation, and thus reduces T cell activation. We further showed that engineering the active PDZ domain of PATJ into CAR structure significantly promoted the effector function of CAR-T cells. Conclusions Our study reveals an important role of PATJ in the formation of IS and provides an approach to improve the efficacy of CAR-T therapy.
Precision enhancement of CAR-NK cells through non-viral engineering and highly multiplexed base editing
Authors: Minjing Wang, Joshua B Krueger, Alexandria K Gilkey, Erin M Stelljes, Mitchell G Kluesner, Emily J Pomeroy, Joseph G Skeate, Nicholas J Slipek, Walker S Lahr, Patricia N Claudio Vázquez, Yueting Zhao, Jason B Bell, Kendell Clement, Ella J Eaton, Kanut Laoharawee, Jae-Woong Chang, Beau R Webber, Branden S Moriarity
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Natural killer (NK) cells’ unique ability to kill transformed cells expressing stress ligands or lacking major histocompatibility complexes (MHC) has prompted their development for immunotherapy. However, NK cells have demonstrated only moderate responses against cancer in clinical trials. Methods Advanced genome engineering may thus be used to unlock their full potential. Multiplex genome editing with CRISPR/Cas9 base editors (BEs) has been used to enhance T cell function and has already entered clinical trials but has not been reported in human NK cells. Here, we report the first application of BE in primary NK cells to achieve both loss-of-function and gain-of-function mutations. Results We observed highly efficient single and multiplex base editing, resulting in significantly enhanced NK cell function in vitro and in vivo. Next, we combined multiplex BE with non-viral TcBuster transposon-based integration to generate interleukin-15 armored CD19 chimeric antigen receptor (CAR)-NK cells with significantly improved functionality in a highly suppressive model of Burkitt’s lymphoma both in vitro and in vivo. Conclusions The use of concomitant non-viral transposon engineering with multiplex base editing thus represents a highly versatile and efficient platform to generate CAR-NK products for cell-based immunotherapy and affords the flexibility to tailor multiple gene edits to maximize the effectiveness of the therapy for the cancer type being treated.
Maintenance of remission after tocilizumab withdrawal in patients with glucocorticoid‐dependent polymyalgia rheumatica
Authors: Baptiste Chevet, Aghiles Souki, Emmanuel Nowak, Guillermo Carvajal‐Alegria, Emmanuelle Dernis, Christophe Richez, Marie‐Elise Truchetet, Daniel Wendling, Eric Toussirot, Aleth Perdriger, Jacques‐Eric Gottenberg, Renaud Felten, Bruno Fautrel, Anne Lohse, Laurent Chiche, Pascal Hilliquin, Catherine Le Henaff, Benjamin Dervieux, Guillaume Direz, Isabelle Chary‐Valckenaere, Divi Cornec, Dewi Guellec, Thierry Marhadour, Alain Saraux, Valérie Devauchelle‐Pensec
Journal: Arthritis & Rheumatology (2025)

Objective The SEMAPHORE trial evaluated the efficacy and safety of tocilizumab (TCZ) in glucocorticoid (GC)‐dependent polymyalgia rheumatica (PMR). TCZ reduced GC use and disease activity at 24 weeks. This study aimed to assess relapse rates after stopping TCZ in patients achieving remission at week 24. Methods In the randomized study, 101 patients received intravenous TCZ (8 mg/kg) or placebo for 24 weeks. Of the 49 TCZ‐treated patients, 33 achieved the primary outcome (PMR‐activity score &lt;10 and GC reduction of ≤5 mg/day or ≥10 mg). All 33 patients except one stopped TCZ at week 24, completed a visit at week 32, with optional follow‐up visits every 8 weeks until week 48. Relapse was defined as the failure of the primary composite outcome during follow‐up or the need for ≥1 TCZ infusion. Results were analyzed using Kaplan–Meier curves. Results Among the 33 patients who received TCZ in remission at week 24, seven stopped follow‐up before the 48 th week, and two of the remaining 26 subjects (7.7%) sustained remission in the following 6 months. 24 (92.3%) of the total patients experienced relapse. The median time to relapse was 15 weeks (interquartile range: 8–25). Conclusion Among patients with GC‐dependent PMR, in remission after a 6‐month TCZ treatment, only a minority of the patients remained relapse‐free after TCZ discontinuation. This study suggests that a 6‐month treatment course is not a long enough to withdraw the TCZ. Further studies are needed to determine the optimal TCZ treatment duration and strategies for cessation to prevent relapses.
[68Ga]-DOTATOC PET/CT and Clear Cell Renal Cell Carcinoma Metastasis: Simple False Positive or Potential Staging Imaging?
Authors: Nicolas Jacquet-Francillon, Sibel Isal, Isabelle Morelec, Chawki Ghayor, Mathilde Vergoby, Anthime Flaus
Journal: Clinical Nuclear Medicine (2025)

Clear cell renal cell carcinoma is the most common type of kidney cancer. Apart of lymph nodes, the frequent metastatic sites are lung, bone and, more rarely, pancreas. These three sites of involvement are also common for NETs. This well-differentiated tumour has a low FDG avidity. We report two clinical cases of pancreatic and pulmonary lesions, suspicious of NET but with a history of clear cell renal cell carcinoma. [68Ga]-DOTATOC PET/CT find strong uptakes but biopsies ultimately revealed metastases of clear cell renal cell carcinoma.