Blood advances最新文献

{"title":"Use of Affimer Technology for Inhibition of α2-antiplasmin and Enhancement of Fibrinolysis.","authors":"Nikoletta Pechlivani, Basmah Alsayejh, Mansour Khalaf Almutairi, Katie Simmons, Thembaninkosi Gaule, Fladia Phoenix, Noppadol Kietsiriroje, Sreenivasan Ponnambalam, Cedric Duval, Robert A S Ariëns, Christian Tiede, Darren C Tomlinson, Ramzi Ajjan","doi":"10.1182/bloodadvances.2024014235","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024014235","url":null,"abstract":"<p><p>Hypofibrinolysis is a documented abnormality in conditions with high risk of vascular occlusion. A key inhibitor of fibrinolysis is α2-antiplasmin (α2AP) and we hypothesise that the Affimer technology, comprising small conformational proteins with two nine amino acid variable regions, can be used to modulate α2AP activity and facilitate fibrinolysis. Using a phage display system, a library of Affimers was screened against α2AP. A total of 28 α2AP-specific Affimers were isolated of which one, termed Affimer A11, inhibited protein function and enhanced fibrinolysis. Affimer A11 displayed a monomeric form and consistently reduced lysis time of clots made from plasma samples of individuals with type 2 diabetes mellitus (n=15; from 150.8±100.9 to 109.8±104.8 mins) and those with cardiovascular disease (n=15; 117.6±40.6 to 79.7±33.3 mins); p<0.01 for both groups. The effects of A11 on fibrinolysis were maintained when clots were made from whole blood samples. Mechanistic studies demonstrated that A11 did not affect clot structure or interfere with incorporation of α2AP into fibrin networks but significantly enhanced plasmin activity and accelerated plasmin generation. Affimer A11 reduced α2AP binding to plasmin(ogen), while molecular modelling demonstrated interactions with α2AP in an area responsible for binding to plasminogen, explaining the effects on both plasmin activity and generation. Affimer A11, at 0.15-0.60 mg/ml, had the ability to bind 70-90% of plasma α2AP. In conclusion, we demonstrate that Affimers are viable tools for inhibiting α2AP function and facilitating fibrinolysis, making them potential future therapeutic agents to reduce thrombosis risk.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590117","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":"Global outcomes and prognosis for relapsed/refractory mature T-cell and NK-cell lymphomas: Results from PETAL consortium.","authors":"Jessy Xinyi Han, Min Jung Koh, Leora Boussi, Mark Sorial, Sean Michael McCabe, Luke Peng, Shambhavi Singh, Ijeoma Julie Eche-Ugwu, Judith Gabler, Maria J Fernandez Turizo, Caroline T MacVicar, Aditya Ramesh Garg, Alexander Disciullo, Kusha Chopra, Alexandra W Lenart, Emmanuel Nwodo, Jeffrey A Barnes, Min Ji Koh, Eliana C M Miranda, Carlos Sergio Chiattone, Robert N Stuver, Steven M Horwitz, Mwanasha H Merrill, Eric D Jacobsen, Martina Manni, Monica Civallero, Tetiana Skrypets, Athina Lymboussaki, Massimo Federico, Yu Ri Kim, Jin Seok Kim, Jae Yong Cho, Thomas Eipe, Tanuja Shet, Sridhar Epari, Alok Shetty, Saswata Saha, Hasmukh Jain, Manju Sengar, Carrie Van Der Weyden, H Miles Prince, Ramzi Hamouche, Tinatin Muradashvili, Francine M Foss, Marianna Gentilini, Beatrice Casadei, Pier Luigi Zinzani, Takeshi Okatani, Noriaki Yoshida, Sang Eun Yoon, Won Seog Kim, Girisha Panchoo, Zainab Mohamed, Estelle Verburgh, Jackielyn Cuenca Alturas, Mubarak Al-Mansour, Josie Ford, Maria Elena Cabrera, Amy Ku, Govind Bhagat, Helen Ma, Ahmed Sawas, Khyati Maulik Kariya, Makoto Iwasaki, Forum Bhanushali, Owen A O'Connor, Enrica Marchi, Changyu Shen, Devavrat Shah, Salvia Jain","doi":"10.1182/bloodadvances.2024014674","DOIUrl":"10.1182/bloodadvances.2024014674","url":null,"abstract":"<p><p>Variances in global access to drugs and treatment practices make it challenging to understand the benefit of contemporary therapies in patients with relapsed and refractory (R/R) mature T-cell and NK-cell lymphomas (MTCL and MNKCL). We conducted an international retrospective cohort study of 925 patients with R/R MTCL and MNKCL. In PTCL-NOS and ALK- ALCL, patients with relapsed lymphoma demonstrated a superior median overall survival (OS) relative to refractory from the time of second-line treatment. We identified several independent predictors of OS for R/R lymphoma including age >60, primary refractory disease, histological subtype other than AITL, extranodal sites >1, Ki67 ≥40%, and absolute lymphocyte count <LLN. A multivariable model incorporating these formed the basis for a prognostic index for R/R TCL (PIRT), in which patients are stratified into low-risk (0-1 risk factor), intermediate-risk (2-3 risk factors), or high-risk (≥4 risk factors) groups, which were associated with 3-year OS of 57.14% (95% CI: 17.1-83.7), 23.3% (8.7-41.9), and 7% (0.4-26.9), respectively. Patients received either a \"novel\" single agent (SA, 35%) or cytotoxic chemotherapy (CC, 60%) for their second line treatment. Higher progression-free survival was observed with SA over CC for the entire cohort with a higher 3-year OS in AITL and ALK- ALCL. Among the SA, small molecule inhibitors demonstrated OS advantage relative to CC in AITL. Our results underscore efficacy of novel drugs and the potential of a new prediction model in informing heterogeneous prognosis within the R/R population of MTCL and MNKCL.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557216","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":"Epigenetic features support the diagnosis of B-cell prolymphocytic leukemia and identify two clinico-biological subtypes.","authors":"Stella Charalampopoulou, Elise Chapiro, Ferran Nadeu, Thorsten Zenz, Silvia Beà, Marta Aymerich, Ares Martinez-Farran, Maria Rozman, Damien Roos-Weil, Olivier A Bernard, Santos A Susin, Helen Parker, Renata Walewska, Christopher C Oakes, Jonathan C C Strefford, Elías Campo, Estella Matutes, Martí Duran-Ferrer, Florence Nguyen-Khac, Jose Ignacio Martin-Subero","doi":"10.1182/bloodadvances.2024013327","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024013327","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543798","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":"Development of iPSC-derived human bone marrow organoid for autonomous hematopoiesis and patient-derived HSPC engraftment.","authors":"Kehan Ren, Ermin Li, Inci Aydemir, Yijie Liu, Xu Han, Honghao Bi, Pan Wang, Kara Tao, Amy Ji, Yi-Hua Chen, Jing Yang, Madina Sukhanova, Peng Ji","doi":"10.1182/bloodadvances.2024013361","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024013361","url":null,"abstract":"<p><p>Current efforts in translational studies in hematology often rely on immunodeficient mouse models for engrafting patient-derived hematopoietic stem and progenitor cells (HSPCs), yet these models often face challenges in effectively engrafting cells from patients with various diseases, such as myelodysplastic syndromes (MDS). In this study, we developed an induced pluripotent stem cell (iPSC)-derived human bone marrow organoid model that closely replicates the bone marrow microenvironment, facilitating the engraftment of MDS patient-derived HSPCs, thereby mirroring the patients' distinct disease characteristics. Specifically, through advanced microscopy, we verified the development of a complex three-dimensional network of endothelial, stromal, and hematopoietic cells within the organoids, resembling the autonomous human marrow microenvironment. Furthermore, we showed that HSPCs derived from the donor bone marrow of normal individuals or patients with MDS can migrate to and proliferate within the organoid's vascular niche while maintaining self-renewal and original genetic profiles. Within the organoids, the differentiation patterns from MDS HSPCs were significantly distinct compared to the multilineage hematopoiesis from normal HSPCs, which can be correlated with the clinical manifestations of the disease. These findings underscore the significance of the organoid model in studying human hematopoiesis and the pathophysiology of hematologic diseases, offering new avenues for personalized medicine and therapeutic interventions.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543796","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":"Lymphopenia Predicts Poor Outcomes in Newly Diagnosed Multiple Myeloma.","authors":"Grace Marie Ferri, Cenk Yildirim, Nhan V Do, Mary T Brophy, Joseph Park, Nikhil C Munshi, Nathanael R Fillmore, Camille V Edwards","doi":"10.1182/bloodadvances.2024014125","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024014125","url":null,"abstract":"<p><p>Bone marrow microenvironment plays an important role in promoting growth and survival of multiple myeloma (MM) cells. The tumor-promoting immune microenvironment is augmented while anti-tumor immune responses are inhibited. Although clinical and genomic markers of high-risk MM have been described, the immune status is just being recognized as a potential mediator of disease behavior. This is even more important with the development of a number of immune-based therapies. Based on these considerations, we evaluated peripheral blood absolute lymphocyte count (ALC) as an easily accessible marker representing immune microenvironment at diagnosis and following treatment of MM. We retrospectively evaluated 11,427 patients diagnosed with MM between 2000 and 2019 at Veteran's Administration hospitals using ALC obtained closest to diagnosis and up to 2.5 years thereafter. Patients were stratified into 3 ALC categories: severely low, low, and normal (<1, 1-1.5, and >1.5 x 103/mm3, respectively). Lymphopenia (including severely low and low ALC) was present in 53% of patients at MM diagnosis and was associated with inferior overall survival (OS). Median OS of patients with severely low, low, and normal ALC at diagnosis was 2.7, 3.3, and 4.2 years (P < .001), respectively. Moreover, persistent or new development of lymphopenia during treatment and follow-up was also associated with inferior OS. Our findings support the use of ALC as a biomarker for risk stratification in MM.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543800","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":"Cancer cachexia and weight loss prior to CAR T-cell therapy for lymphoma are independently associated with poor outcomes.","authors":"Yannis K Valtis, Sean M Devlin, Roni Shouval, Kai Rejeski, Magdalena Corona, Alejandro Luna De Abia, Alfredo Rivas-Delgado, Efrat Luttwak, Giulio Cassanello, Ivan Landego, Heiko Schöder, Akshay Bedmutha, Alexander P Boardman, Gunjan L Shah, Michael Scordo, Miguel-Angel Perales, Gilles A Salles, M Lia Palomba, Urvi A Shah, Jae H Park","doi":"10.1182/bloodadvances.2024014555","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024014555","url":null,"abstract":"<p><p>CAR T-cell therapy has transformed the care of lymphoma, yet many patients relapse. Several prognostic markers have been associated with CAR T cell outcomes, such as tumor burden, response to bridging chemotherapy, and laboratory parameters at the time of lymphodepletion or infusion. The effect of cancer cachexia and weight loss prior to CAR T cells on toxicity and outcomes is not well understood. Here, we present a retrospective single institution cohort study of 259 patients with lymphoma treated with CAR T-cells between 2017 and 2023. We observed that patients with a >5% decrease in their body mass index (BMI) in the 3 months preceding CAR T treatment (weight loss group; all meeting one of the commonly accepted definitions of cancer cachexia) had higher disease burden and inflammatory parameters (CRP, ferritin, IL6, TNFa) at time of lymphodepletion and CAR T-cell infusion. Patients with weight loss experienced higher rates of grade 3+ neurotoxicity and early hematotoxicity but those effects were not seen upon multivariable adjustment. However, in both univariate and multivariable analysis, patients with weight loss had worse response rates, overall survival, and event-free survival, indicating that weight loss is an independent poor prognostic factor. Our data suggest that weight loss in the 3 months preceding CAR T-cell therapy represents a worrisome \"alarm signal\" and potentially modifiable factor alongside tumor burden and inflammation and warrants further investigation in patients treated with CAR T therapy.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543795","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":"Hematopoietic Cell Transplant compared with Standard Care in Adolescents and Young Adults with Sickle Cell Disease.","authors":"Mark C Walters, Mary Eapen, Yiwen Liu, Fuad El Rassi, Edmund K Waller, John E Levine, John J Strouse, Joseph H Antin, Suhag H Parikh, Nitya Bakshi, Carlton D Dampier, Jennifer J Jaroscak, Shayla Bergmann, Trisha E Wong, Vamsi K Kota, Betty Sue Pace, Lazaros J Lekakis, Premal D Lulla, Robert Nickel, Kimberly A Kasow, Uday R Popat, Wally R Smith, Lolie C Yu, Nancy L DiFronzo, Nancy L Geller, Naynesh Kamani, Elizabeth Sue Klings, Kathryn Hassell, Adam M Mendizabal, Keith Sullivan, Donna S Neuberg, Lakshmanan Krishnamurti","doi":"10.1182/bloodadvances.2024013926","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024013926","url":null,"abstract":"<p><p>Disease-modifying therapies are standard of care (SOC) for sickle cell disease (SCD), but hematopoietic cell transplantation (HCT) has curative potential. We compared outcomes prospectively through 2-years after biologic assignment to a Donor or No Donor (SOC) Arm based on the availability of an HLA-matched sibling or unrelated donor (BMTCTN 1503; NCT02766465). A donor search was commenced after eligibility confirmation. The primary endpoint was the comparison of survival 2 years after biologic assignment between treatment arms. Power calculations required 60 participants on the Donor Arm and 140 on the No Donor Arm to determine if early transplant-related mortality might be balanced by disease-related mortality over a longer period of follow-up. Secondary objectives compared changes in SCD-related events, functional outcomes, and organ function. Data were analyzed by the intent-to-treat principle. A total of 113 participants were enrolled, 28 on the Donor and 85 on the No Donor Arm The 2-year probabilities of survival were 89% and 93%, on the Donor and No Donor Arms, respectively. Vaso-occlusive pain (VOC) was less frequent on the Donor Arm in the second year after biologic assignment (p < 0.001). On PROMIS-57 surveys there was decreased fatigue (p=0.003) and an increased ability to participate in social roles and activities (p=0.003) on the Donor Arm 2-years after biologic assignment. Differences in other secondary outcomes did not reach statistical significance. Barriers to accrual prevented an objective comparison of survival. Assignment to the Donor Arm led to improvements in VOC, fatigue, and social function.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543799","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":"The E3 ubiquitin ligase MARCH5 promotes mitochondrial fusion and cell cycle progression in acute myeloid leukemia.","authors":"Clement Larrue, Sarah Mouche, Jérôme Tamburini","doi":"10.1182/bloodadvances.2024013890","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024013890","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543801","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":"Achieving Equitable Care in Pulmonary Embolism: Exploring the Potential of Pulmonary Embolism Response Teams.","authors":"Lidiya Sul, Akiva Rosenzveig, Fahad Alkhalfan, Gerald J Bishop, Pulkit Chaudhury, Leben Tefera","doi":"10.1182/bloodadvances.2024014616","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024014616","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543794","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":"Divergent Modulation of Activated Protein C Pleiotropic Functions by Antibodies That Differ by A Single Amino Acid.","authors":"Derek S Sim, Meenal Shukla, Cornell R Mallari, José A Fernández, Xiao Xu, Douglas Schneider, Maxine Bauzon, Terry W Hermiston, Laurent O Mosnier","doi":"10.1182/bloodadvances.2024013584","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024013584","url":null,"abstract":"<p><p>Activated protein C (APC) is a pleiotropic plasma protease with diverse functions derived from its anticoagulant, anti-inflammatory, and cytoprotective activities. The selective uncoupling and/or modulation of these APC activities by antibodies may have therapeutic benefit in diseases such as traumatic bleeding, hemophilia, sepsis, and ischemia. TPP-26870 is an antibody that targets a non-active site of APC for the selective modulation of APC activities. To optimize the potency of TPP-26870, variants with single amino acid mutation in the complementarity-determining regions (CDRs) were screened, and 21 variants with improved KD were identified. Interestingly, the affinity maturation of TPP-26870 did not merely generate a panel of variants with higher potency in functional assays. Functional data demonstrated that the pleiotropic functions of APC were very sensitive to epitope-CDR interactions. Single amino acid mutations within the CDRs of TPP-26870 were sufficient to elicit divergent antagonistic and agonistic effects on the various APC functional activities. These include prolonged in vitro APC plasma half-life, increased inhibition of anticoagulant activity, and agonistic enhancement of histone H3 cleavage, while having less impact on PAR1 cleavage in comparison to TPP-26870. This study illustrates that APC is highly sensitive to non-active site targeting that can lead to unpredictable changes in its activity profile of this pleiotropic enzyme. Further, this study demonstrates the ability to modify APC functions to advance the potential development of APC targeted antibodies as therapeutics for the treatment of diseases including trauma bleeding, hemophilia, ischemia, and sepsis.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543797","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}