bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stapled BAD BH3 Helices Effectively Target BCL-2 Mutants That Cause Venetoclax Resistance
Authors: Deangelo Thomas M. , Adhikary Utsarga , Korshavn Kyle J. , Brotzen-Smith Clara R. , Seo Hyuk-Soo , Song Kijun , Sebastian Luke , Dhe-Paganon Sirano , Wales Thomas E. , Bird Gregory H. , Walensky Loren D. 
Published: December 2024

Background and Rationale: BCL-2 is the founding member of a family of proteins that regulate apoptosis by controlling the integrity of the mitochondrial outer membrane. BCL-2 intercepts and traps the critical BH3 helices of BAX and BAK in a groove on the protein surface, blocking BAX/BAK-mediated apoptosis. Venetoclax is a selective small molecule inhibitor that binds within the BCL-2 groove and restores the apoptotic pathway by neutralizing the capacity of BCL-2 to inhibit BAX and BAK, effectively “inhibiting an inhibitor” of apoptosis (Souers et al., Nat Med 2013). As the clinical use of venetoclax has expanded, resistance mutations in BCL-2 have arisen that thwart venetoclax binding yet preserve native BH3 interactions, thus re-establishing apoptotic blockade (Blombery et al., Blood 2020). Here, we harnessed the capacity to stabilize the secondary structure of native, bioactive alpha-helices by all-hydrocarbon stapling (Walensky et al., Science 2004) to develop and interrogate BH3 helices that bind venetoclax-resistant mutants of BCL-2 with high affinity and restore BCL-2 inhibition.
Results and Conclusions: We screened a library of “stapled” BH3 peptides modeled after the BAD BH3-only protein, which selectively engages the anti-apoptotic proteins BCL-2, BCL-XL, and BCL-w. We identified lead alpha-helical constructs that retain the ability to potently target and functionally inhibit BCL-2 irrespective of venetoclax resistance mutations. We performed a series of structural analyses that revealed both the conformational consequences of BCL-2 mutagenesis and the mechanistic basis for retention of high-affinity binding by lead stapled BAD BH3 peptides. These compounds provide prototypes for the development of next-generation BCL-2 inhibitors that overcome resistance to small molecule treatment.
Risks and Harms to Physicians Reporting Hematologic Adverse Drug Reactions (ADRs) to Health Authorities
Authors: Bennett Charles , Watson Gretchen , Knopf Kevin , Martin Linda , Gale Robert Peter 
Published: December 2024

Background : The Southern Network on Adverse Reports group (SONAR) has previously identified severe risks and harms to physicians who reported serious ADRs to Heath Authorities related to solid-tumor oncology pharmaceuticals. (eClinMed, PLOS One, Journal of Scientific and Professional Integrity) We investigated whether similar risks and harms occurred to clinicians/scientists who reported hematology-associated ADRS.
Methods: Quotes were abstracted from media coverage or Health Authority hearings for individual hematology drugs.
Results : Risks and harms were reported in regulatory agency or government agency meetings by eight clinician/scientists physicians who led phase-3 pharmaceutical-sponsored clinical trials (Olivieri N (U Toronto, NEJM 1996, Singh G, Stanford, unpublished 2004), Buse J (U of North Carolina, unpublished 1999, Henke M (Abteilung Universitatsklinik, Lancet 2003, Mangano D (UCSF, NEJM 2005), Topol E and Nissen S (Cleveland Clinic JAMA 2004), meta-analyses (n = 2) (Bennett C (Northwestern, JAMA 2008, Mangano D (UCSF, NEJM 2006); database analyses (n = 1) (Mangano D (UCSF, NEJM 2004), case-control studies (n = 1) (Brass L, Yale, NEJM 2005) and an independent safety review (n = 1) (Solomon S, Harvard, JAMA 2005) including lawsuits, loss of job, public harassment and loss of grants. Three physicians lost academic positions (Topol, Olivieri, Mangano), two physicians lost federal grants (Olivieri, Bennett), and one FDA scientist (Graham) was demoted. ADR findings resulted in drug removal (n = 7; Vioxx, Avandia, Bextra, Celebrex, Trasylol, Phenyl propanolamine, Hydroxy-ethyl starch), revised indications (n = 2) (Procrit, Aranesp 2007, 2008, 2010)) or 10-year delay in FDA-approval (n = 1) (Fereprox). Median time from FDA approval to ADR identification was 8 years (Range, 4 years (Bextra) to 62 years PPA)). Numbers of persons reportedly seriously injured or dying from 1 ADR was 10,00 (Procrit)- 270,000 (Vioxx) (median 120,000). Manufacturer allegations that resulted in pharmaceutical companies actions included violation of secrecy agreement (n = 2) (Fererpox, PPAs) and public reporting of proprietary data (n = 11). Pharmaceutical companies paid $600,000 (Fereprox) to $5.8 billion (Vioxx) in fines and settlements.
Discussion: Twelve physicians experienced severe threats and/or harms after reporting hematologic-associated ADRs to Health Authorities and/or in major publications. We suggest physicians not sign secrecy agreements that might jeopardize public safety (as currently established by almost all US medical universities) and should partner with independent drug safety monitoring boards (DSMBs) on ADR evaluations to monitor safety concerns of drugs and medical devices.
Correlations between Lesion Avidity, Immune Effector Cell-Associated Neurotoxicity Syndrome Scoring, and Fracture Risk in Patients with Multiple Myeloma Undergoing Chimeric Antigen Receptor T-Cell Therapy
Authors: Clampitt Bryan , Huynh Thien Huong , Chose Chloe Min , Nester Mathew Daniel , Kuruvilla Davis , Joyce David , Binitie Odion , Freeman Ciara Louise , Lazarides Alexander 
Published: December 2024

Background :
Patients with refractory multiple myeloma (MM) may be eligible for chimeric antigen receptor T-cell (CAR-T) therapy. Such patients are monitored for treatment toxicities, commonly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Patients' skeletal disease may also be characterized by lesion avidity and categorized by fracture risk. The purpose of the present study is to evaluate the associations between treatment toxicity, fracture, and pre-CAR-T lesion avidity in MM patients.
Methods :
A prospective, consecutive cohort of (MM) patients undergoing treatment with CAR-T therapy were reviewed retrospectively. The primary outcome measure was fracture risk as characterized by a modified Mirel's criteria. The secondary outcome measure was change in lesion avidity, measured as standardized uptake value (SUV) units, on PET-CT. Correlations were performed using Pearson and Spearman correlations.
Results :
We identified 139 patients who underwent CAR-T for multiple myeloma. The mean age was 64.4 years with 58 female patients (41.7%). There was a negative correlation between ICANS Toxicity Grade and days survived (rs=-0.322, p&lt;0.02) and positive correlation with the lesion SUV measurements prior to CAR-T (rs=0.375, p&lt;0.01). No significant correlations were found with CRS. The SUV of lesions prior to CAR-T had positive correlations with pre-CAR-T Mirel's criteria of size (rs=0.196, p&lt;0.035), nature(rs=0.362, p&lt;0.000), pain(rs=0.303, p&lt;0.001), and overall score (rs=0.327, p&lt;0.000) of the lesions. There were positive correlations between fracture occurrence with pre-CAR-T Mirel's criteria of size (rs=0.362, p&lt;0.000), nature (rs=0.219, p&lt;0.012), pain(rs=0.393, p&lt;0.000), and overall score(rs=0.394, p&lt;0.000) of the lesions. Pre-CAR-T SUV values were positively correlated with fracture occurrence (rp=0.205, p&lt;0.025)
Conclusions:
Our findings suggest that SUV measurements may have some association with fractures and ICANS grade in MM patients undergoing CAR-T. While SUV may correlate with Mirel's criteria, it is not as strongly correlated with fractures.
Prospective Evaluation of the Prevalence of Pulmonary Embolism in Patients with Chronic Obstructive Pulmonary Disease Exacerbation: Challenges and Feasibility
Authors: Mai Vicky , Fergusson Dean , Le Gal Gregoire , Mulpuru Sunita 
Published: December 2024

Introduction: Data on the prevalence of pulmonary embolism (PE) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in North America is lacking, with most of the prospective studies conducted in Europe and Asia. The aim of this study is to describe feasibility of prospective collection of data evaluating the prevalence of PE in patients admitted for AECOPD in Canada, and to describe challenges of this approach.
Methods: This is a secondary analysis of a prospective pilot patient cohort aiming to assess the diagnosis of AECOPD among hospitalized patients. Items of the Wells PE and revised Geneva scores were prospectively collected. All patients underwent D-dimer testing within 24 hours of admission. All patients were followed for 3 months. Feasibility outcomes were prospective data collection to evaluate the prevalence of PE, D-dimer level measurement and 3-month follow-up. The study was considered feasible if &gt;=90% of the patients had prospective data collected to assess the prevalence of PE, &gt;=80% of the patients had D-dimer level measured and their 3-month follow-up, respectively. Challenges were also assessed.
Results: Twenty patients were included. According to the Wells PE score, 16 (80.0%), 4 (20.0%) and 0 (0.0%) patients had low, moderate and high clinical pre-test probability (c-PTP), respectively. According to the revised Geneva score, 2 (10.0%), 17 (85.0%) and 1 (5.0%) patients had low, intermediate and high c-PTP, respectively. Based on age-adjusted D-dimer cut-off, 7 and 11 patients had negative and positive D-dimer, respectively. All patients (100.0%) had prospective data collection to assess the prevalence of PE. D-dimer level was available for 18/20 (90.0%) patients and 3-month follow-up evaluation was performed in 16/20 (80.0%) patients. Challenges included the difficulty in recruiting patients since it is a population with many comorbidities, adequate c-PTP assessment using validated clinical decision rules, absence of consistent PE diagnostic strategy use since patients were mostly investigated according to the physician's impression and adequate 3-month follow-up since 25% of the patients had some protocol deviation for the follow-up. No PE was diagnosed during the entire study period.
Conclusion: This pilot study shows the feasibility in prospectively collecting data to evaluate the prevalence of PE in patients admitted for AECOPD in Canada. Also, challenges were assessed and included recruitment of patients, adequate c-PTP assessment, consistent PE diagnostic strategy use and adequate 3-month follow-up.
Sequential Infusion of Anti-CD19 and Anti-BCMA Chimeric Antigen Receptor T-Cells: A Promising Treatment Strategy for Refractory Immune-Mediated Platelet Transfusion Refractoriness
Authors: Ma Yunju , Cui Qingya , Yang Chunxiu , Cui Wei , Li Mengyun , Li Zheng , Dai Haiping , Kang Liqing , Yu Lei , Tang Zaixiang , Fu Jianxin , Jiang Min , Wu Depei , Tang Xiaowen 
Published: December 2024

Background: Immune-mediated platelet transfusion refractoriness (iPTR) represents a challenging, high-cost, and life-threatening problem among patients with hematological malignancies. Refractory iPTR (riPTR), which exhibits resistance to multiple therapeutic plasma exchange, high dose of IgG and rituximab, may result from incomplete elimination of allo-specific B cells and long-lived plasma cells. Therefore, sequential anti-CD19 and anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cells were used to treat riPTR.
Methods: In this prospective single-arm clinical trial, patients with riPTR received a combination of murine anti-BCMA CAR T-cells and murine anti-CD19 CAR T-cells at a dose of 2×107 cells/kg. The efficacy and safety of this treatment were assessed. This study was registered at clinicaltrials.gov (identifier: NCT04846439).
Results:Twelve patients with riPTR received CAR T-cell treatment with a median follow-up of 33.5 (range, 13.5-34.5) months. Among these 12 patients, the median of the maximum mean fluorescence intensity (MFI) values of anti-human leukocyte antigen (HLA) antibodies decreased by 91.1%, from 15319 (range, 10807-20374) before CAR T-cell infusion to 1369 (range, 997-2923) at 4 months post-infusion (P=0.0001). And four months after CAR T-cell infusion, the median number of anti-HLA class I antibodies with an MFI &gt; 5000 decreased significantly from 18 (range, 3-41) before infusion to 0 (range, 0-0) post-infusion (P=0.0005). Anti-HLA antibodies in all patients turned negative within 5 months after CAR T-cell therapy and have maintained negative for up to 30.5 months to date. After CAR T-cell treatment, the medians of the amount of platelet transfusions within 7 days and the duration of platelet count below 10×109/L were significantly lower (P = 0.0002, P = 0.001). Meanwhile, there was a significant increase in 14-hour corrected count increment (CCI) and no occurrence of 14-hour CCI below 5×109/L in all patients after the administration of CAR T-cells. RiPTR was completely corrected in all patients and never occurred during subsequent chemotherapy or transplantation. All patients who underwent transplantation achieved successful neutrophil and platelet engraftment. No patient developed grade ≥ 3 cytokine release syndrome. All patients experienced transient grade ≥ 3 cytopenia. Only 2 patients (16.7%) experienced infection. All adverse events were reversible and manageable.
Conclusions:CAR T-cell therapy could be well-tolerated and highly effective in overcoming riPTR and eradicating allo-antibodies, making it applicable to antibody-mediated diseases.
Runx1+23 Enhancer Reporter Marks Erythro-Megakaryocyte Lineages in Human ESC Differentiation Culture
Authors: Syed Alina , Nishida Chika , Kobayashi Michihiro , Wenzel Pamela L. , Davis Brian , Yoshimoto Momoko 
Published: December 2024

Runx1 is an essential transcriptional factor for hemogenic endothelial cells (HECs) to transit to hematopoietic stem/progenitors in mammalian embryos. In mice, it has been shown that Runx1 +23kb enhancer region (Runx1+23) marks HECs in the embryo and HSCs in the adult bone marrow (BM) specifically.
In order to identify HECs in human embryonic stem cell (ESC) differentiation culture, we utilized Runx1+23 enhancer-reporter hESC lines; H9 Runx1+23 Ds-Red and H1 Runx1+23 venus. We differentiated these Runx1+23 ESCs into hematopoietic lineage on laminin coated plate. We examined CD34+CD43- EC and CD34+CD43+ hematopoietic progenitor (HPC) productions as well as CD235a+ RBC and CD43+CD41 megakaryocyte production on day 6, day 8, and day 10 culture. We found robust Runx1+23+ Ds-Red (denoted Runx1+23) expression on CD235a+ RBCs, CD43+CD41+ cells, and CD34+CD43+ HPCs. However, Runx1+23 expression was not detected in CD34+CD43- EC population. When we gated Run1+23 population, they were relatively large, did not express CD144 EC markers, but expressed CD43 and CD41. Cytospin preparation of sorted Runx1+23+ cells showed that Runx1+23+ cells contained megakaryocytes and erythroblast. We also sorted Runx1+23 positive or Runx1+23 negative CD34+CD43+ HPCs or CD34+CD43-ECs and plated them onto Methylcellulose culture to test colony forming ability and onto MS5 stromal cells for testing B cell potential. Runx1+23+ cells displayed a greater number of megakaryocytes colony-forming cells compared to Runx1+23 negative cells and expressed erythro-megakaryocyte genes including GATA1, GATA2, TAL1, and hemoglobin genes. On MS5 cell co-culture, only Runx1+23 negative ECs produced CD19+B-cells and CD56+ NK cells. Finally, scRNA-sequencing of day 10 differentiation culture revealed that Runx1+23+ cells were exclusively expressed in the erythro-megakaryocytes populations.
These results indicated that Runx1+23 enhancer region is exclusively active in erythro-megakaryocyte lineage specification in human ESC differentiation culture, different from mouse system, suggesting different usage of Runx1+23 enhancer region between mice and humans.
R-CVP in Nodular Lymphocyte Predominant Hodgkin Lymphoma in Children
Authors: VU Thi An , Olivier Laura , Simonin Mathieu , Boudjemaa Sabah , Jonca Bénédicte , Rigaud Charlotte , Garnier Nathalie , Mansuy Ludovic , Curtillet Catherine , Treguier Pauline , Neumann Florent , Heritier Sebastien , Dourthe Marie-Emilie , Landman-Parker Judith 
Published: December 2024

Introduction : A strategy of therapeutic de-escalation has been proposed for children with localized stage nodular lymphocyte predominant Hodgkin Lymphoma (NLPHL) over the past twenty years : either local surgical treatment and watch and wait after complete resection of an isolated adenopathy or low intensity chemotherapy ±Rituximab (R). Here, we provide results on the management and efficacy of R-CVP in children with early stage NLPHL.
Methods : A retrospective multicenter national study was carried out in the centers of the French Children's Cancers Society (SFCE) to evaluate the tolerability and efficacy of 3 courses of Rituximab 375 mg/m2-Cyclophosphamide (500 mg/m2 day 1), Vinblastine 6 mg/m2 day 1 and 8, Prednisolone (40 mg/m2 day 1-8) (R-CVP) treatment in NLPHL patients under 18 years of age diagnosed between January 2015 and December 2023. NLPHL diagnosis was confirmed by hematopathologist review and the staging was evaluated by FDG-TEP/CT in all patients.
Results : Twelve children, median age at diagnosis 12 years, (range 7-16 years); boys n=10 received R-CVP between January 2019 and December 2023 in SFCE centers. No patient were treated by R-CVP before 2019 in France. Patients were classified as stage IA n=4 , stage IIA n=7 and stage IIIA n=1. Six patients were treated by R-CVP as first line treatment at initial diagnosis, 3 cases for residual adenopathy post initial surgery, 3 cases after relapse (median time to relapse 9 months) after primary treatment by local surgery and/or radiotherapy. All patients achieved complete remission. In 10/12 cases R-CVP course was performed every 21 days, only one patient received R-CVP every 15 days. Stage IIIA received 4 courses of R-CVP. With a median follow up of 23 months (8-45 months) EFS and OS is 100%. Forty-two percent presented neutropenia at d17 (nadir 0.3 G/l and 0.6 G/l first and third course, respectively). No patient needed blood transfusion support. Grade II mucositis and febrile neutropenia were reported as well as grade I/II peripheral sensitive neuropathy, constipation or digestive disorders
Conclusion: Our results show that R-CVP is an effective chemotherapy regimen in children with localized stage NLPHL. Limited hematological toxicities and peripheral neuropathy were reported during the treatment
DOCK1 Expression Enhances the Activity of the Notch Signaling Pathway and Promotes the Proliferation and Survival of Acute Myeloid Leukemia Cells
Authors: Lin Ming-En , Hsu Yueh-Chwen , Chiu Hsueh-Ling , Yao Chi-Yuan , Liu Chia-Hua , Kao Chein-Jun , Li Chang-I , Yuan Chang-Tsu , Yang Yi-Tsung , Hou Hsin-An , Chou Wen-Chien , Tien Hwei-Fang 
Published: December 2024

In spite of recent advances in genetic risk categorization and treatment, the available options for patients of acute myeloid leukemia (AML) resistant to standard chemotherapy remain limited. There is an urgent need to address this problem. In a prior study, we identified DOCK1 gene expression as an independent prognostic marker by means of microarray analysis of gene expression in an AML cohort adopting the ELN 2010 risk stratification. To validate the prior results and explore deeper into the molecular mechanisms, we analyzed the clinical impacts of DOCK1 expression on a new cohort of 341 de novo non-M3 AML patients diagnosed from February 2004 to December 2016. These patients were risk-stratified using the 2022 ELN classifications, and we utilized more advanced RNA sequencing technology for our analysis. All of the patients were treated with standard chemotherapy. We demonstrate that higher DOCK1 expression still correlates with unfavorable cytogenetics and mutations, and it is an independent adverse prognostic factor.
We subsequently investigated its pathogenesis using cell lines, xenograft models, and a hematopoietic cell-specific Dock1-conditional knockout model in mice. Cell line experiments showed positive roles of DOCK1 in proliferation and viability. This observation is further corroborated by xenograft experiments, in which mice transplanted with DOCK1-knockdown cells had longer survival times than those engrafted with control cells. Although mice with a hematopoietic cell-specific knockout of Dock1 exhibited minimal phenotypic changes, the loss of Dock1 ameliorated MN1-induced AML in vivo. Transcriptome analyses of cell lines and human samples consistently revealed upregulation of NOTCH signaling pathway in cells with higher DOCK1 expression, as evidenced by higher expression levels of HES1, a direct downstream target of NOTCH pathway. Single-cell RNA sequencing of MN1-induced mouse leukemia cells within Dock1-conditional knockout background also revealed a unique cluster of cells that predominantly existed in DOCK1-wild type rather than Dock1-conditional knockout mice and exhibited the highest expression of DOCK1, MN1, and HES1 among all clusters. These cells showed upregulation of stem cell function, G2M checkpoint, E2F targets, and Myc signaling pathways, consistent with the phenotypes of DOCK1 in our study. Our findings highlight the role of DOCK1 expression in the pathogenesis of AML and suggest DOCK1 as a potential therapeutic target for this group of patients.