bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blocking IL1RAP on cancer-associated fibroblasts in pancreatic ductal adenocarcinoma suppresses IL-1-induced neutrophil recruitment
Authors: Hansen Nils , Peña-Martínez Pablo , Skoog Petter , Reinbach Katrin , Hansen Finja C , Faria Susanne Larsson , Grönberg Caitríona , Abdilleh Kawther , Magnusson Susanne , von Wachenfeldt Karin , Millrud Camilla Rydberg , Liberg David , Järås Marcus 
Published: December 2024

BackgroundPancreatic ductal adenocarcinoma (PDAC) represents a major clinical challenge due to its tumor microenvironment, which exhibits immune-suppressive properties that facilitate cancer progression, metastasis, and therapy resistance. Interleukin 1 (IL-1) signaling has been implicated as a driver in this process. Mechanistically, both IL-1α and IL-1β bind to the IL-1 receptor type 1, forming a complex with IL-1-receptor accessory protein (IL1RAP), which triggers downstream signaling pathways. The IL1RAP blocking antibody nadunolimab is currently in clinical development, but the precise consequences of inhibiting IL-1 signaling in PDAC remains elusive.MethodsTo evaluate the biological relevance of blocking IL1RAP using nadunolimab in a PDAC animal model, human PDAC cells and cancer-associated fibroblasts (CAFs) were co-transplanted into mice. To study the underlying mechanisms of IL1RAP blockade ex vivo, co-cultured PDAC cells and CAFs were treated with nadunolimab prior to RNA sequencing. Migration assays were performed to assess how nadunolimab affects interactions between CAFs and myeloid immune cells. Finally, to establish a clinical correlation between IL1RAP expression and nadunolimab treatment effects, we analyzed tumor biopsies from a clinical phase I/II study in which nadunolimab was administered to patients.ResultsIn the xenograft mouse model, nadunolimab exhibited antitumor effects only when human CAFs were co-transplanted with PDAC cells. IL-1 stimulation induced CAFs to secrete chemokines that recruited neutrophils and monocytes. The secretion of this chemokine and the migration of myeloid cells were inhibited by nadunolimab. Media conditioned by IL-1-stimulated CAFs sustained a neutrophil population with a tissue invasion phenotype, an effect that was reversed by nadunolimab. In a cohort of metastatic late-stage PDAC patients receiving nadunolimab as monotherapy, high IL1RAP expression in tumors was associated with extended progression-free survival.ConclusionsOur study demonstrates that targeting IL1RAP on CAFs inhibits IL-1-induced chemokine secretion and recruitment of neutrophils and monocytes, thereby counteracting the immunosuppressive microenvironment in PDAC. These findings highlight the therapeutic potential of targeting IL1RAP in PDAC.
Personalized neoantigen hydrogel vaccine combined with PD-1 and CTLA-4 double blockade elicits antitumor response in liver metastases by activating intratumoral CD8+CD69+T cells
Authors: Tang Shichuan , Tang Ruijing , Chen Geng , Zhang Da , Lin Kongying , Yang Huan , Fu Jun , Guo Yutong , Lin Fangzhou , Dong Xiuqing , Huang Tingfeng , Kong Jie , Yin Xiaowei , Ge Aimin , Lin Qizhu , Wu Ming , Liu Xiaolong , Zeng Yongyi , Cai Zhixiong 
Published: December 2024

BackgroundLiver metastasis is highly aggressive and immune tolerant, and lacks effective treatment strategies. This study aimed to develop a neoantigen hydrogel vaccine (NPT-gels) with high clinical feasibility and further investigate its efficacy and antitumor molecular mechanisms in combination with immune checkpoint inhibitors (ICIs) for the treatment of liver metastases.MethodsThe effects of liver metastasis on survival and intratumor T-cell subpopulation infiltration in patients with advanced tumors were investigated using the Surveillance, Epidemiology, and End Results Program (SEER) database and immunofluorescence staining, respectively. NPT-gels were prepared using hyaluronic acid, screened neoantigen peptides, and dual clinical adjuvants [Poly(I:C) and thymosin α-1]. Then, the efficacy and corresponding antitumor molecular mechanisms of NPT-gels combined with programmed death receptor 1 and cytotoxic T-lymphocyte-associated protein 4 double blockade (PCDB) for the treatment of liver metastases were investigated using various preclinical liver metastasis models.ResultsLiver metastases are associated with poorer 5-year overall survival, characterized by low infiltration of cytotoxic CD8+T cells and high infiltration of regulatory T cells (Tregs). NPT-gels overcame the challenges faced by conventional neoantigen peptide vaccines by sustaining a durable, high-intensity immune response with a single injection and significantly improving the infiltration of neoantigen-specific T-cell subpopulations in different mice subcutaneous tumor models. Importantly, NPT-gels further combined with PCDB could enhance neoantigen-specific T-cell infiltration and effectively unlock the immunosuppressive microenvironment of liver metastases, showing superior antitumor efficacy and inducing long-term immune memory in various preclinical liver metastasis models without obvious toxicity. Mechanistically, the combined strategy can inhibit Tregs, induce the production and infiltration of neoantigen-specific CD8+CD69+T cells to enhance the immune response, and potentially elicit antigen-presenting effects in Naïve B_Ighd+cells and M1-type macrophages.ConclusionsThis study demonstrated that NPT-gels combined with PCDB could exert a durable and powerful antitumor immunity by enhancing the recruitment and activation of CD8+CD69+T cells, which supports the rationale and clinical translation of this combination strategy and provides important evidence for further improving the immunotherapy efficacy of liver metastases in the future.
Adenoviral-vectored neoantigen vaccine augments hyperexpanded CD8+T cell control of tumor challenge in mice
Authors: Dagotto Gabriel , Colarusso Alessandro , Patio Robert C , Li David , Anioke Tochi , Giffin Victoria , Guan Ruoran , Anand Trisha , Mbiwan Esther , Aid Malika , Barouch Dan 
Published: December 2024

BackgroundNeoantigens are promising immunogens for cancer vaccines and are often delivered as adjuvanted peptide vaccines. Adenoviral (Ad) vectors have been shown to induce strong CD8+T cell responses as vaccines against SARS-CoV-2, Ebola, and Zika, but their utility as neoantigen delivery vectors remains largely unexplored. In this study, we examine how an Ad-vectored neoantigen vaccine would impact tumor immunity compared with a peptide neoantigen vaccine.MethodsWe generated Ad serotype 26 (Ad26) vaccine candidates encoding B16-F10-ovalbumin (OVA) and MC38-specific neoantigens. Ad26 vaccines were compared with adjuvanted peptide delivery as prophylactic vaccines in B16-F10-OVA and MC38 challenge models. Immune responses induced by the best Ad26 vaccine (Ad26.VP22.7Epi) were compared with peptide vaccination systemically and within the tumor. Following vaccination with Ad26.VP22.7Epi, peptide, or sham, tumor-infiltrating CD45+cells were analyzed using single-cell RNA sequencing (scRNA-seq) and T cell receptor sequencing (TCR-seq) to identify vaccine-induced differences in the tumor microenvironment.ResultsSingle-shot Ad26 vaccines induced greater neoantigen-specific interferon-γ CD8+T cell immune responses than two-shot adjuvanted peptide vaccines in mice, and Ad26.VP22.7Epi also provided superior protective efficacy compared with the peptide vaccine following tumor challenge. Ad26.VP22.7Epi induced a robust immunodominant CD8+T cell response against the Adpgk neoantigen, while the peptide vaccine-induced lower responses against both Adpgk and Reps1 neoantigens. scRNA-seq analysis of CD45+tumor-infiltrating cells demonstrated that both Ad26.VP22.7Epi and peptide vaccine-induced similar numbers of infiltrating CD8+T cells. However, Ad26.VP22.7Epi induced CD8+T cells showed more upregulation of T cell maturation, activation, and Th1 pathways compared with peptide vaccine induced CD8+T cells, suggesting improved functional T cell quality. TCR-seq of these tumor-infiltrating lymphocytes also demonstrated that Ad26.VP22.7Epi generated larger T cell hyperexpanded clones compared with the peptide vaccine.ConclusionsThese results suggest that the Ad26.VP22.7Epi vaccine led to improved tumor control compared with the peptide vaccine due to increased T cell hyperexpansion and functional activation. Our data suggest that future cancer vaccine development strategies should focus on inducing functional hyperexpanded CD8+T cell responses and not only maximizing tumor infiltrating CD8+T cell numbers.
What can we learn from machine learning studies on flow diverter aneurysm embolization? A systematic review
Authors: Bayraktar Esref Alperen , Cortese Jonathan , Jabal Mohamed Sobhi , Ghozy Sherief , Orscelik Atakan , Bilgin Cem , Kadirvel Ramanathan , Brinjikji Waleed , Kallmes David F 
Published: December 2024

BackgroundAs the use of flow diverters has expanded in recent years, predicting successful outcomes has become more challenging for certain aneurysms.ObjectiveTo provide neurointerventionalists with an understanding of the available machine learning algorithms for predicting the success of flow diverters in occluding aneurysms.MethodsThis study followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the four major medical databases (PubMed, Embase, Scopus, Web of Science) were screened. The study included original research articles that evaluated the predictive abilities of various machine learning algorithms for determining the success of flow diverters in achieving aneurysm occlusion.ResultsFive studies out of 217 were included based on our criteria. The included studies used various variables (patient demographics, aneurysm and parent artery characteristics, flow diverter and hemodynamic-related features, and angiographic parametric imaging) to predict flow diverter treatment outcomes. The machine learning algorithms used, along with their respective accuracy rates, were as follows: logistic regression (61% and 85%), support vector machine (88%), Gaussian support vector machine (90%), linear support vector machine (85%), decision tree (80%), random forest (87%), k-nearest neighbors (83% and 85%), XGBoost (87%), CatBoost (86%), deep neural networks (77.9%), and recurrent neural networks (74%).Two studies trained the machine learning models with both all features and the most significant features. Both studies observed that the accuracy of machine learning models decreased by removing the insignificant features.ConclusionThe current literature indicates that machine learning algorithms can be trained to predict the success of flow diverters with an accuracy of up to 90%.
Vessel wall MRI evaluation for the safety of endovascular recanalization of non-acute intracranial anterior circulation artery occlusions
Authors: Meng Yao , Yang Yun , Magigi Miyengi Cosmas , Li Weili , Song Yun , Zhao Wei , Zheng Meimei , Sun Lili , Yin Hao , Wang Wei , He Xiao , Zhang Jun , Han Ju 
Published: December 2024

BackgroundVessel wall MRI (VWMRI) can reveal the morphological features of intracranial artery occlusion (ICAO). This study aimed to investigate the imaging features of ICAO on VWMRI and explore their correlation with perioperative complications of endovascular recanalization for non-acute ICAO.MethodsThe study retrospectively included consecutive patients with recurrent ischemic stroke due to non-acute ICAO in the anterior circulation who underwent preoperative VWMRI evaluation and endovascular recanalization. Perioperative complications included ischemic and hemorrhagic strokes within 30 days after operation. Imaging features of the occluded segments were evaluated on precontrast and post-contrast VWMRI, including occlusion length and site, vessel wall area, signal intensity, angle, and shape of the occluded segment. The associations between the clinical and imaging features and perioperative complications were examined.ResultsOne hundred and four patients were included in the analysis, of whom 22.1% (23/104) had perioperative complications. After adjusting for multiple confounding variables, four imaging risk factors were identified that were independently associated with perioperative complications, that is, the angle between the occluded and pre-occluded artery segments (OR 11.60, 95% CI 2.73 to 49.29), occluded artery segment shape (OR 13.07, 95% CI 2.82 to 60.67), vessel wall collapse before occlusion (OR 2.91, 95% CI 0.96 to 8.77), and post-contrast mean signal intensity ratio at the ¼ point of the occluded artery segment <1.24 (OR 6.14, 95% CI 1.67 to 22.51). From no risk factors to four risk factors, the incidence of perioperative complications gradually increased (0, 6.2%, 23.5%, 52.9%, and 100% respectively; p<0.001).ConclusionsVWMRI may be helpful to select patients with non-acute ICAO who are suitable for endovascular recanalization.
CT perfusion for lesion-symptom mapping in large vessel occlusion ischemic stroke
Authors: Garrard James William , Neuhaus Ain , Carone Davide , Joly Olivier , Zarrintan Armin , Rabinstein Alejandro A , Huynh Thien , Harston George , Brinjikji Waleed , Kallmes David F 
Published: December 2024

BackgroundIdentifying eloquent regions associated with poor outcomes based on CT perfusion (CTP) may help inform personalized decisions on selection for endovascular therapy (EVT) in patients with large vessel occlusion (LVO) ischemic stroke. This study aimed to characterize the relationship between CTP-defined hypoperfusion and National Institutes of Health Stroke Scale (NIHSS) subitem deficits.MethodsPatients with anterior circulation LVO, baseline CTP, itemized NIHSS at presentation and 24 hours were included. CTP was analyzed using e-CTP (Brainomix, UK). Time to maximal contrast (Tmax) prolongation was defined as >6 s, and penumbra as the difference between Tmax and ischemic core (relative cerebral blood flow<30%). Voxel-lesion-symptom mapping was performed using sparse canonical correlation analysis. For each NIHSS subitem, and total NIHSS, the associations were plotted between Tmax voxels with baseline NIHSS, and penumbra voxels with delta NIHSS (24 hours minus baseline).ResultsThis study included 171 patients. Total NIHSS was predicted by hypoperfusion in left frontal cortex and subcortical white matter tracts. Voxels associated with neurological recovery were symmetrical and subcortical.Limb deficits were associated with respective motor cortex regions and descending motor tracts, with negative correlation within the contralateral hemispheres. A similar but smaller cluster of voxels within the penumbra was associated with NIHSS improvement. Language impairment correlated with left frontal cortex and superior temporal gyrus voxels. With the exception of dysarthria, significant associations were observed and more diffusely distributed in all other NIHSS subitems.ConclusionsThese results demonstrate the feasibility of hypoperfusion-to-symptom mapping in LVO. Symptom-based mapping from presenting imaging could refine treatment decisions targeting specific neurological deficits.
Elective outpatient middle meningeal artery embolization for chronic subdural hematoma is safe
Authors: McGrath Margaret , Gallagher Aaron , Raub Spencer , Carroll Kate T , Abecassis Zachary A , Ruiz Rodriguez Juan Francisco , Philbrick Brandon D , Kellner Christopher P , Sioutas Georgios S , Scott Kyle , Srinivasan Visish M , Burkhardt Jan-Karl , Shaikh Hamza A , Khalife Jane , Tonetti Daniel A , Lam Nicholas , Ares William J , Gomez-Paz Santiago , Budohoski Karol , Grandhi Ramesh , Levitt Michael R 
Published: December 2024

BackgroundMiddle meningeal artery embolization (MMAE) is a safe and effective treatment for chronic subdural hematoma (cSDH); however, the appropriate level of postoperative care is unknown.ObjectiveTo evaluate whether elective MMAE for cSDH could be safely performed in an outpatient setting.MethodsThis was a multicenter, retrospective study of patients with cSDH who underwent elective MMAE. Patients were categorized as either inpatient (admitted for ≥1 night of hospitalization after MMAE) or outpatient (discharged on the same day of MMAE). Patient demographics, radiological data, procedural details, and follow-up data were collected. The primary endpoint was periprocedural complications, and secondary outcomes included emergency department (ED) visits or unplanned readmission within 24 hours, 1–7 days, and 8–30 days after MMAE.ResultsElective MMAE procedures were carried out in 190 patients, of which 45.3% (n=86) were outpatient procedures and 54.7% (n=104) inpatient. There were 7 (3.7%) periprocedural complications (one outpatient, six inpatient; P=0.12). Five patients presented to the ED and were readmitted within 24 hours of MMAE (three outpatient, two inpatient). Six patients presented to the ED 1–7 days after MMAE (three outpatient, three inpatient); three were subsequently admitted (one outpatient and two inpatient). Nine patients presented to the ED 8–30 days after MMAE (two outpatient and seven inpatient); three were subsequently readmitted (all inpatient). No elective outpatient MMAE resulted in a readmission attributable to the procedure within the examined time frame.ConclusionElective MMAE can be safely performed as an outpatient procedure without increased risk of postprocedural adverse events in most eligible patients with cSDH.
Enhancing thrombectomy outcomes with Adaptive Pulsatile Aspiration (APA): the role of complete clot ingestion in reducing thrombectomy time and distal embolization
Authors: Lu Victor M , Thompson John , Elarjani Turki , Jaman Emade , Sherman Josiah , Hanser Manning , Abuawad Mazen , Limaye Kaustubh , Guerrero Waldo R , Vakharia Kunal , Walzman Daniel , Abecassis Isaac Josh , De Leacy Reade Andrew , Crowley R Webster , Starke Robert M 
Published: December 2024

BackgroundComplete clot ingestion (CCI) is defined as full ingestion of the clot into the catheter or pump canister without any external clot remnants at the catheter tip. The aim of this study was to demonstrate that using the CCI metric in vitro, partially ingested (‘corked’) clots pose a higher risk of distal emboli given distal emboli may exist in the setting of Thrombolysis In Cerebral Infarction 3 (TICI 3) revascularization.MethodsThrombectomies using an in vitro synthetic clot analog were conducted across six catheters using the novel ALGO Smart Pump with Adaptive Pulsatile Aspiration (APA) (Von Vascular Inc, Sunrise, FL) and compared against the Penumbra static Engine Pump (Alameda, CA).ResultsA total of 360 aspiration thrombectomies were completed with an overall CCI rate of 56.9%. Cases achieving CCI were significantly faster (P<0.001) and those with successful CCI had no instances of distal embolization, whereas cases with incomplete clot ingestion (‘corking’) showed a 5.2% rate of distal embolization (P<0.001). The overall rate of first pass effect was comparable between two systems. ALGO’s APA mode achieved a significantly higher rate of CCI compared with the Penumbra Engine Pump’s continuous aspiration (77.2% vs 36.7%, P<0.001), as well as shorter mean aspiration (43.7 s vs 73.2 s, P<0.001). Additionally, these trends were also reflected across all individually tested catheter types between the pump systems.ConclusionsOur findings demonstrate that CCI is a feasible and valuable metric for assessing thrombectomy efficacy in vitro, resulting in more favorable CCI outcomes with the ALGO system compared with the Penumbra system.
How well do plasma Alzheimer’s disease biomarkers reflect the CSF amyloid status?
Authors: Hazan Jemma , Abel Emily , Rosa Grilo Miguel , Alawode Deborah , Laranjinha Ines , Heslegrave Amanda J , Liu Kathy Y , Schott Jonathan M , Howard Robert , Zetterberg Henrik , Fox Nick C 
Published: December 2024

BackgroundCan plasma biomarkers as well as cerebrospinal fluid (CSF) perform in the separation of amyloid-beta-positive (Aβ+) vs amyloid-beta-negative (Aβ−) groups across an age range seen in an NHS cognitive disorder clinic?MethodsAs part of the routine diagnostic investigation of 111 clinic patients who had contemporaneous blood and CSF samples taken, patients were categorised into Aβ+ and Aβ− groups based on their CSF in an Aβ42/40 ratio. We then evaluated four single molecule array (Simoa) Quanterix assays, quantifying single plasma analytes and ratios (p-tau217, p-tau217/Aβ42 ratio, p-tau181, p-tau181/Aβ42 ratio and Aβ42/40 ratio) in their ability to distinguish between these groups and the effect of age.ResultsThe median (range) age of participants was 66 (55–79) years with 48 females (43.2%). The areas under the curve (AUC), not accounting for age, for the ability to discriminate Aβ+ from Aβ− groups were plasma p-tau217 AUC=0.94, Aβ42/40 AUC=0.78 and p-tau181 AUC=0.77. Combining p-tau217/Aβ42 increased the AUC to 0.97. The difference between the groups was influenced by age with less separation in older individuals: a significant negative interaction term between age and group for plasma p-tau217 concentrations (−0.037, p=0.013) and p-tau217/Aβ42 ratio (−0.007, p=0.008).ConclusionsThere was variable performance of plasma biomarkers to recapitulate the CSF assay. Both p-tau217 and p-tau217/Aβ42 showed excellent promise as surrogates of CSF amyloid status, although with slightly reduced performance in older individuals. There was poorer discriminatory ability for p-tau181 and Aβ42/40. Further research is needed to address potential age-related confounds.
Left atrial appendage occlusion in patients with atrial fibrillation and intracerebral haemorrhage associated with cerebral amyloid angiopathy: a multicentre observational study and pooled analysis of published studies
Authors: Thiankhaw Kitti , Best Jonathan , Srivastava Sonal , Prachee Ishika , Agarwal Smriti , Tan Serena , Calvert Patrick A , Chughtai Asim , Ang Richard , Segal Oliver R , Werring David J 
Published: December 2024

BackgroundCerebral amyloid angiopathy (CAA) is a common cause of intracerebral haemorrhage (ICH) with a high recurrence risk. Left atrial appendage occlusion (LAAO) is a method for ischaemic stroke prevention in patients with atrial fibrillation (AF), potentially reducing the risk of intracranial bleeding in CAA-associated ICH. We aimed to determine the outcomes of patients with AF with CAA-associated ICH undergoing LAAO.MethodsWe conducted a multicentre study of patients with CAA-associated ICH who underwent LAAO for stroke prevention. We pooled our findings with data from a systematic review of relevant published studies of LAAO for AF in ICH survivors reporting CAA diagnosis.ResultsWe included data from two published studies (n=65) with CAA-specific data and our cohort study (n=37), providing a total of 102 participants (mean age 76.2±8.0 years, 74.6% male) with CAA-related symptomatic ICH and AF treated with LAAO. The median follow-up period was 9.4 months (IQR 4.2–20.6). Postprocedural antithrombotic regimens varied between single (73.0%) or dual antiplatelet therapy (16.2%), or direct oral anticoagulant (DOAC) (10.8%), with a median duration of 42 days (IQR 35–74). Postprocedural complications were uncommon, but included transient arrhythmias (2.1%) and non-life-threatening tamponade (2.1%). Pooled incidence rates of ischaemic stroke and ICH during follow-up were 5.16 (95% CI 1.36 to 17.48) and 2.73 (95% CI 0.41 to 13.94) per 100 patient years, respectively.ConclusionsLAAO followed by short-term antithrombotic therapy might be a safe and effective ischaemic stroke preventive strategy in people with CAA-associated ICH and AF. However, randomised controlled trials are needed to determine how LAAO compares with long-term DOAC in this population.PROSPERO registration numberCRD42023415354.