Blood advances最新文献

{"title":"In situ gene editing of hematopoietic stem cells via AAV-delivered CRISPR guide RNAs.","authors":"Alborz Karimzadeh, Rebekah Kim, Vivian Garcia, Michael Florea, Bryan L Peacker, Shio Kobayashi, Drake Watkins, Kathleen A Messemer, Jing Zeng, Daniel E Bauer, Thomas Serwold, Amy J Wagers","doi":"10.1182/bloodadvances.2025016775","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025016775","url":null,"abstract":"<p><p>Hematopoietic stem cells (HSCs) are self-renewing, multipotent, and engraftable precursors of all blood cells. Efficient delivery of therapeutic gene products and gene editing machinery to correct disease-causing gene variants in endogenous HSCs while they remain in the body holds exciting potential to leverage HSC potency for the treatment of monogenic blood disorders. Towards this goal, we used adeno-associated virus (AAV) to deliver CRISPR guide RNAs (gRNAs) to edit HSC genomes in situ in Ai9;SpCas9-EGFP transgenics carrying a Cas9-activatable Lox-STOP-Lox (LSL)-tdTomato reporter cassette together with a constitutive SpCas9-2A-EGFP. Using a variety of conditions and vector designs, we tested whether systemic administration to these mice of AAVs carrying SpCas9 compatible gRNAs designed to cut DNA upstream and downstream of the STOP cassette would induce tdTomato expression in HSCs. Our findings identify self-complementary AAVs (scAAVs) and increased guide to Cas9 ratio as parameters facilitating higher editing efficiency. Of note, we find preserved multilineage output and engraftability of HSCs upon scAAV-gRNA editing. In an example application of this technology, we explore the potential for in situ HSC gene editing by dual AAV-CRISPR delivery and demonstrate robust gene modification, concurrent with induction of therapeutic fetal hemoglobin (HbF), in a sickle cell disease (SCD) mouse model modified to express SpCas9. In summary, this work offers a sensitive and adaptable platform that allows robust modification of HSC genomes in situ.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Soluble Urokinase Plasminogen Activator Receptor and Acute Kidney Injury in Hematopoietic Cell Transplantation.","authors":"Bhavna Bhasin-Chhabra, Tao Wang, John E Levine, Shalini Shenoy, Miguel-Angel Perales, Asad Bashey, Hershel Raff, Wael Saber","doi":"10.1182/bloodadvances.2025016655","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025016655","url":null,"abstract":"<p><p>Acute kidney injury (AKI) frequently follows hematopoietic cell transplantation (HCT). Soluble urokinase-type plasminogen activator receptor (suPAR) is a biomarker of AKI in the general population. We evaluated suPAR and its association with AKI requiring dialysis (AKI-D) in patients undergoing allogeneic HCT (alloHCT). Performance of suPAR was compared to serum creatinine (sCr) and neutrophil gelatinase-associated lipocalin (NGAL). Data were obtained from Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1202 cohort (NCT01879072), an observational study of 1,709 alloHCT recipients. Adults aged 18 or older with AKI-D post HCT were included. Adults who did not develop AKI were included as controls and matched 1:1. Periodic serum samples (7-90 days) were analyzed for NGAL, suPAR, and sCr. The 1:1 matched case-control groups (n = 62 each) were balanced in demographic variables, except for graft-versus-host disease (GVHD) prophylaxis. The median time from transplant to AKI-D was 2.6 months (range 0.03-20.39). Day +7 suPAR after HCT was higher in patients with AKI (median 2.7 ng/mL) compared to controls (2.1 ng/mL) (P = .002). In multivariate analysis, day +7 suPAR was associated with development of AKI-D (P = .009). The area under the curve for the receiver operating characteristic curve for day +7 suPAR levels was 0.75. Neither NGAL nor sCr were associated with AKI-D. Elevated day +7 suPAR levels predicted AKI and lower overall survival (OS). suPAR at day +7 post HCT may be an early prognostic factor for development of AKI-D and OS. Future, prospective studies could evaluate this at different stages of AKI.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Outcomes with Third Party Virus Specific T-cells After the Use of Single Antigen Cell Lines to Predict HLA Restriction.","authors":"Jeremy D Rubinstein, Giang Pham, Anusha Sridharan, Ruby Khoury, YunZu Michele Wang, Zahra Hudda, Jamie Wilhelm, Daniel Lichtenstein, Daria Heyenbruch, Jose A Cancelas, Stella M Davies, Carolyn Lutzko, Michael Grimley","doi":"10.1182/bloodadvances.2025017097","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025017097","url":null,"abstract":"<p><p>Patients with significant T-cell dysfunction from chemotherapy or hematopoietic stem cell transplant are at significant risk for complications of viral infections. Off-the-shelf third-party virus specific T-cells (TP VSTs) are an effective and well tolerated treatment for the management of infection with adenovirus (ADV), BK polyomavirus (BKV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV). TP VST product selection for any particular patient incorporates maximizing the number of human leukocyte antigen (HLA) matches between the product and the patient along with consideration of the anti-viral activity of the product. We have previously shown that single antigen cell lines (SALs), cell lines expressing a single HLA molecule, can be used in a flow cytometric based assay to determine sites of HLA restriction for TP VST products. We hypothesized that incorporating match at sites of HLA restriction into TP VST product selection would improve response rates. Here we report on 25 patients who received TP VSTs for the treatment of 26 viral infections with at least one match at an HLA restricted site. In this cohort the overall response rate was 96.2% with a complete response rate of 69.2%. These data suggest the annotation of VST banks to include SAL derived HLA restriction could lead to improved product selection and efficacy. NCT02532452 Clinicaltrials.gov.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patient-reported outcomes in patients with hematologic malignancies treated with CAR T-cell therapy in Europe.","authors":"Elise Ra Pennings, Anne Mea Spanjaart, Frederick W Thielen, Simone Oerlemans, Anna Fleischer, Carmen Sanges, Maria Gomes Da Silva, Yolanda Cabrerizo, Pacôme Lecot, Lutgart Roux-Opstaele, Caroline Dreuillet, Eglys Gonzalez-Marcano, Olga Millán, Ulrich Jaeger, Julio Delgado, Maik Luu, Barbara Huber, Margot Lorrain, Mariana Galhardas Pina, Andreas Kremer, Natacha Bolanos, Solène Clavreul, Samantha Nier, Roberto D K Liu, Birgit I Lissenberg-Witte, Sébastien Anguille, Marie Robin, Emma C Morris, Anna Sureda, Marie Préau, Myriam Pannard, Geertruida H De Bock, Scott S Wagers, Hélène Trebeden-Negre, Delphine Maucort-Boulch, Michael Hudecek, Carin A Uyl-de Groot, Marie José Kersten","doi":"10.1182/bloodadvances.2025017081","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025017081","url":null,"abstract":"<p><p>Patient-reported outcomes (PROs) give direct insights into the treatment's impact on patient's life and are an essential addition to clinical outcomes. However, since the advent of CAR T-cell therapy (CAR-T), PROs have been underreported. Particularly little is known about long-term health-related quality of life (HRQoL) and dimensions as mental- and social wellbeing, working-life and financial burden. Therefore, we evaluated multidimensional PROs in a cross-sectional study among European patients who received CAR-T for hematologic malignancies. Patients completed validated questionnaires (EQ-5D-5L/EORTC-QLQ-C30/PCL-5/modified-iPCQ) and ad hoc items on treatment experiences, unmet care needs and HRQoL. The survey was available online (January-October 2023) in 7 languages. Outcomes were compared with the European general population, a matched CAR-T naive cohort with hematologic malignancies and across subgroups, using established thresholds for clinically important differences/problems and regression models. Patients from 10 European countries participated (N=389; CAR-T>1 year ago:56%). Mean EQ-VAS and EQ-index were 73.1(SD:18.5) and 0.842(SD:0.177). HRQoL was similar/better than reference cohorts, except for role-, social-, and cognitive-functioning. Physical-functioning problems were most frequently reported(41%), particularly by women, elderly, and those who experienced neurotoxicity. The latter subgroup also reported more cognitive- and social-functioning problems. Anxiety regarding disease recurrence(76%), infections(66%) and long-term side-effects(59%) was common and 4% met provisional PTSD-diagnosis criteria. Among working-age patients, 72% could continue paid work after CAR-T. Younger patients(32%) reported more financial difficulties than older patients(9%). This study shows favorable general HRQoL after CAR-T compared to reference cohorts. However, a notable proportion of patients experienced problems in physical-, mental- and social wellbeing. We identified high-risk subgroups and care needs that should be addressed during CAR-T follow-up.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Androgen receptor signaling as a new target for intervention in acute myeloid leukemia.","authors":"Fenghua Qian, Deborpita Sarkar, Brooke E Arner, Vanessa M Peduzzi, Yuting Bai, Baiye Ruan, Bei Jia, Hong Zheng, Robert F Paulson, K Sandeep Prabhu","doi":"10.1182/bloodadvances.2024012639","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024012639","url":null,"abstract":"<p><p>In addition to their role in development, sex hormones and their cognate receptors play an important role in various malignancies. Using a murine model of human MLL-AF9 induced acute myeloid leukemia (AML), we discovered that high Androgen receptor (AR) expressing leukemia initiating cells (LICs) when transferred into either male or female recipients resulted in more severe disease than low AR-expressing LICs. AR expression was significantly increased in female LICs compared to male LICs. This difference was confined to the LICs and not present in normal bone marrow cells. AML cells from both sexes relied on AR signaling via different mechanisms-females had high AR with low ligand, males, low AR with high ligand. AR expression was linked to EPHA7-associated PI3K/AKT/MTOR and SRC/HIF-1α pathways. Use of the two US FDA approved drugs for prostate cancer, ARN509, an AR antagonist and finasteride, which inhibits the pathway that produces dihydrotestosterone, resulted in significant remission with increased survival of AML mice. ARN509 and finasteride also showed pro-apoptotic effect in patient-derived AML cells and in a humanized AML model in NSG mice. These data support a drug repurpose effort to use anti-androgen therapy to improve the efficacy of AML treatments.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age-Based Pegaspargase Dosing is Safe and Achieves Therapeutic Levels in Infants with ALL: Report from COG AALL15P1.","authors":"Kelly E Faulk, John A Kairalla, Emily Hibbitts, Janel R Long-Boyle, Meenakshi Devidas, Amanda August, Lia Gore, Elizabeth A Raetz, Stephen P Hunger, Mignon L Loh, David Trent Teachey, Patrick A Brown, Erin H Breese, Rishi Sury Kotecha, Erin Guest","doi":"10.1182/bloodadvances.2025017013","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025017013","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum TARC: a biomarker for early detection or exclusion of relapse in classic Hodgkin lymphoma.","authors":"Sophie A Teesink, Lydia Visser, Marcel Nijland, Kylie Keijzer, Anne G H Niezink, Bart-Jan Kroesen, Anke van den Berg, Arjan Diepstra, Wouter J Plattel","doi":"10.1182/bloodadvances.2025015837","DOIUrl":"10.1182/bloodadvances.2025015837","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"4618-4621"},"PeriodicalIF":7.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12455077/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comments and concerns on the analysis of DAPS-ITP trial.","authors":"Aarti Vibhakar, Shaan D Shah, Ashwin Patel","doi":"10.1182/bloodadvances.2025017207","DOIUrl":"10.1182/bloodadvances.2025017207","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"4736-4737"},"PeriodicalIF":7.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12496242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BaR-based cryo-EM of platelet integrin αIIbβ3.","authors":"Sneha Singh, Arijit Biswas","doi":"10.1182/bloodadvances.2025017161","DOIUrl":"10.1182/bloodadvances.2025017161","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":"9 18","pages":"4654-4655"},"PeriodicalIF":7.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12496243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Can baseline cytomegalovirus IgG titers predict cytomegalovirus reactivation after ide-cel therapy?","authors":"Taku Kikuchi, Ukyo Kondo, Shotaro Sugita, Miyu Watanabe, Chiaki Matsumoto, Moe Nomura-Yogo, Kodai Kunisada, Haruka Sawada, Kota Sato, Tomomi Takei, Mizuki Ogura, Yu Abe, Kenshi Suzuki, Osamu Hosoya, Tadao Ishida, Nobuhiro Tsukada","doi":"10.1182/bloodadvances.2025017174","DOIUrl":"10.1182/bloodadvances.2025017174","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"4716-4719"},"PeriodicalIF":7.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466258/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}