bluuebunny/crossref_metadata_2025_split huggingface dataset:
RGT-61159, Best-in-Class Small Molecule Inhibitor of MYB Via Selective RNA Splicing Alteration, Showed Robust Anti-Tumor Activity across AML Tumor Models Harboring Common Genetic Lesions
Authors: Lu Norman , Soulard Patricia , Kay Ibrahim , Li Kai , Gu Xiubin , Sadlish Heather , Lee Jay , Elhawary Mariam , Rotelli Michael , Hasson Sam , Wynn Thomas , Yates Chris , Weng Zhiping , Xi Simon , Wager Travis 
Published: December 2024

MYB gene encodes a transcription factor that acts as a master regulator of cells self-renewal, proliferation and differentiation processes. MYB is frequently upregulated or aberrantly activated in a variety of solid cancers (e.g., adenoid cystic carcinoma [ACC], colorectal cancer [CRC], and liquid tumors). In leukemias, high MYB RNA levels are especially frequent (90%) in acute myeloid leukemia (AML). In addition, in T-cell acute lymphoblastic leukemia (T-ALL), MYB is overactivated in 20-30% of patient population due to well characterized genetic lesions (e.g., chromosomal translocations [c-MYB/AHI1; TCRB-MYB 8%], gene duplication [19%]), or somatic mutations. Importantly, a genome-wide CRISPR-Cas9 screen identified MYB as an essential gene for leukemia/lymphoma cell lines viability. Altogether, data strongly suggest MYB as a promising therapeutic target to treat blood cancers.
RGT-61159 is a potent, selective oral small molecule inhibitor of the MYB oncogene via the inclusions of a cryptic exon into MYB RNA transcripts, resulting in the activation of the nonsense-mediated decay pathway promoting MYB mRNA depletion and sequentially MYB protein degradation. RGT-61159 Phase 1 study in adults with relapsed/ refractory ACC or CRC has been initiated (NCT 06462183)
Here, we report RGT-61159 robust MYB RNA & protein knockdown and cell-killing activity across a broad range of different AML cell lines with different oncogenic abnormalities. Such a data set supports that RGT-61159 killing activity of leukemic cells is driven by MYB signaling inhibition and confirms MYB dependency across a broad AML patient population. In addition, we report proteomic and genomic analyses of different AML cell lines treated with RGT-61159 that provided further lights on key oncogenes (e.g., BCL2, NOTCH, MYC) directly regulated by MYB in a cell genetic context dependent.
To further evaluate RGT-61159's potential to treat leukemia, RGT-61159 single agent was profiled in a battery of murine models of AML harboring the most common genetic lesions (e.g., AML-1-ETO, MLL-fusion and NPM1 mutation). RGT-61159 showed highly significant anti-tumor activity across the different AML tumor models tested along with robust MYB RNA depletion in tumor cells (up to 90% tumor growth inhibition [TGI]) in a dose dependent manner and at tolerated doses.
In summary, MYB oncogene represents a therapeutic target of relevance to AML and other hematological malignancies. RGT-61159 is a potent and selective oral small molecule inhibitor of MYB RNA and protein and an attractive therapeutic avenue to treat cancers overexpressing the oncogenic MYB protein.
Markers of Activated Coagulation Factor XII Are Inversely Associated with Progression of Atrial Fibrillation in the Race V Study
Authors: Nagy Magdolna , Weberndoerfer Vanessa , Posma Jens , Van Kuijk Sander , Nguyen Bao-Oanh , Ten Cate Hugo , Van Gelder Isabelle C , Crijns Harry , Rienstra Michiel , Spronk Henri M.H. 
Published: December 2024

Background: Paroxysmal atrial fibrillation (PAF) is a common cardiac arrhythmia which may cause stroke and heart failure, especially in case of AF progression. Recent studies have suggested that hypercoagulability may play a significant role in the pathophysiology of PAF by facilitating initiation and progression of PAF. Most evidence for the hypercoagulable state originates from elevated levels of D-dimer, prothrombin fragment 1+2 or thrombin-antithrombin complexes, however whether this originates from the intrinsic (FXII) or the extrinsic (FVII) pathway is not known. Therefore, we aimed to systematically investigate the association of the activation of single coagulation factors with the progression of AF.
Methods: In this sub-study of RACE V (Reappraisal of Atrial Fibrillation: Interaction between HyperCoagulability, Electrical Remodelling, and Vascular Destabilisation in the Progression of Atrial Fibrillation, NCT02726698) study, 417 patients with PAF were included. At baseline extensive phenotyping was performed including blood samples drawn. During follow-up continuous monitoring for AF progression defined as either development of persistent or permanent AF during follow-up or an increase of &gt;3% AF burden over the first 6 months or total follow-up, was performed for at least one year. Hypercoagulability was monitored through activated coagulation factors (FXIIa, FXIa, FIXa, FXa, pKa and thrombin) in complex with their natural inhibitors (antithrombin (AT), C1-esterase inhibitor (C1Inh), or alpha-1-antitrypsin (a1AT)) utilizing ELISA. Multivariable logistic regression analysis was used for the association of coagulation markers with AF progression.
Results: 51 out of 417 study subjects showed AF progression within the follow-up time period. Patients with AF progression showed significantly lower FXIIa complexes in comparison to patients without AF progression (759 pM [660-879] vs. 886 pM [765-1007]. The activation state of the other coagulation factors showed no statistically significant differences. Multivariate analysis identified that FXIIa complexes (odds ratio [OR] 0.998, 95% confidence intervals [CI] 0.997-0.999, p&lt;.001.) are associated with AF progression. FXIa (OR 0.734, 95%CI 0.521-1.033, p=0.76), FXa (OR 0.532, 95%CI 0.201-1.405, p=0.203), FIXa (OR 1.101, 95%CI 0.789-1.538, p=0.572), thrombin (OR 1.022, 95%CI 0.997-1.048, p=0.086) and kallikrein (OR 0.969, 95%CI 0.903-1.039, p=0.372) showed no relationship with AF-progression.
Conclusion: In patients with PAF FXIIa was inversely related to AF progression. Downstream activation of the intrinsic cascade, however, was not related to AF progression. Whether this means that FXII is over-proportionally auto-activated or has a protective role or in AF-progression needs to be further investigated.
Characteristics and Therapeutic Response of Erdheim-Chester Disease Associated with Myeloid Neoplasm, an Observational Multicenter Study
Authors: Le Pogam Ambroise , Papo Matthias , Hirsh Pierre , Emile Jean-Francois , Duffau Pierre , Razanamahery Jerome , Lazarro Estibaliz , Roos-Weil Damiens , Cohen-Aubart Fleur , Jachiet Vincent , Mekinian Arsene , Fain Olivier , Amoura Zahir , Hadjadj Jerome , Haroche Julien 
Published: December 2024

Introduction : Erdheim-Chester disease (ECD) is L-group histiocytosis with adult-onset and life-threatening multisystemic involvement. ECD is frequently reported in association with clonal hematopoiesis and myeloid neoplasm (MN). Due to its rarity, clinical, hematological, and mutational characteristic of ECD associated with MN, as well as their evolution under targeted therapy, are actually not known.
Methods : We performed a retrospective study of 67 patients with ECD or mixed histiocytosis associated with MN. All data were collected from medical records before and under treatment. Therapeutic response was assessed by CRP and FDG-PET-CT at 6 and 12 months. Characteristics were compared to a control cohort of 348 ECD without MN. The mutational profile was obtained at MN diagnosis and under kinase inhibitor (KI i.e. BRAF and/or MEK inhibitors) through deep targeted sequencing analysis.
Results : A total of 67 patients with ECD and MN were reported, including 33 chronic myelomonocytic leukemia (CMML), 18 with myelodysplastic syndromes (MDS), 15 with myeloproliferative neoplasms (MPN) and one acute myeloid leukemia (AML). MDS cases and CMML cases had low blasts and favorable prognosis score respectively.
ECD patients with MN were significantly older at histiocytosis diagnosis (65 years vs. 59 years, p &lt;0.0001) and exhibited more frequent cardiac (54% vs. 37%, p &lt; 0.01), pulmonary (48% vs. 31%, p &lt; 0.01), perirenal (84% vs. 64%, p = 0.004), and digestive (34% vs. 11%, p &lt; 0.0001) involvement than those without MN. The most frequent myeloid mutations in the cohort were TET2, KRAS, SRSF2, ASXL1, NRAS and CBL. There was an increase in the number of myeloid mutations from 78 to 99 mutations after a mean reassessment time of 25 months under KI. MN progression or transformation occurred in 25% of patients, similarly in those treated with kinase inhibitor or IFN. Median survival-rate of ECD patients with MN was 76 months compared to 163 months in ECD without MN (p &lt; 0.001).
Conclusion : ECD associated with MN affects older patients, with more frequent cardiac, pulmonary, and digestive involvement, as well as increased mortality compared to ECD without MN. Our study shows no evidence of increased risk of progression of underlying myeloid neoplasm under kinase inhibitor.
Temporal Trends and Demographic Disparities in Mortality from Heart Failure with Co-Existing Iron Deficiency Anemia in the United States, 1999-2020
Authors: Zafar Fatima , Najafi Syed Muhammad Ali , Fazal Muhammad Imtanan , Shubhangi Fnu , Mukhtiar Vaibhavi P , Talal Umer , Safdar Malik Ahsan , Manan Muhammad Romail , Nawaz Iqra , Naeem Ammad 
Published: December 2024

Introduction
Heart failure (HF) is a rapidly prevalent issue and affects individuals across diverse demographics. Various comorbidities can exacerbate HF symptoms in certain populations and may predict poorer outcomes. The aim of this study was to conduct a retrospective analysis of mortality trends stratified by gender, race, geographic distribution, and urbanization in HF patients with iron deficiency anemia (IDA).
Methods
The CDC WONDER multiple causes of death database was used for analysis of HF with IDA-related mortality in adults (≥25 years of age) from 1999 to 2020. Age-adjusted mortality rates (AAMRs) per 100,000 population were computed using ICD-10 codes I50 (HF) and D50 (IDA). Joinpoint regression was used to visualize the mortality trends and calculate the average annual percentage change (AAPC) and annual percentage change (APC).
Results
Between 1999 and 2020, HF with IDA caused 7226 deaths in the US adult population. The mortality rate showed an initial decline (1999-2012), but later (2012-2020) a significant up-rising trend was appreciated in the AAMR, with an APC of -2.4% (95% CI: -3.6–1.3, p&lt;0.001) to 13% (95% CI: 11.2-15.5, p&lt;0.001). Males exhibited a consistently higher AAMR with an AAPC of 3.6% (95% CI: 2.6-4.7, p&lt;0.001) against 3.1% (95% CI: 2.4-3.9, p&lt;0.001) in females. The analysis also indicates that the white population has the highest mortality among all races, with an AAMR of 0.16 (95% CI: 0.15-0.16), followed by 0.14 (95% CI: 0.09-0.2) in the American Indian/Alaska Native population. Census records from all the regions showed upward trending, with the West and Northeast regions displaying AAPC values of 3.95% (95% CI: 2.6-5.6, p&lt;0.001) and 3.5% (95% CI: 2.2-5.2, p&lt;0.001), respectively. Stratification based on urbanization displayed a significantly higher mortality trend among the rural population when compared with the urban population.
Conclusion
A significant upsurge has been observed in the mortality trends of HF with IDA in recent years. When stratified by gender, race, census region, and rural/urban area, disparities in mortality rates were observed. This highlights the need to identify vulnerable populations, determine modifiable and non-modifiable variables, and implement proactive healthcare policies aimed at reducing the rising mortality burden among HF patients with IDA.
Efficacy and Safety of Venetoclax Added to Arsenics Plus All-Trans-Retinoic Acid Combination Salvage Regimen for Patients with Relapsed/Refractory Acute Promyelocytic Leukemia
Authors: Lou Yinjun , Jin Jie , Tong Hongyan , Suo Shanshan , Wang Huafeng , Mao Liping , Meng Haitao , Yu Wenjuan 
Published: December 2024

Background: Despite high cure rates in acute promyelocytic leukemia (APL), treatment outcomes in patients with relapsed/refractory (R/R) APL, particular with central nervous system (CNS) involvement relapse remains challenge. Recently, venetoclax (VEN, a selective BCL2 inhibitor) plus azacitidine has shown superior efficacy to azacitidine monotherapy in newly diagnosed unfit patients. However, data of venetoclax in APL patients were Limited. Here, we aim to analysis the efficacy and safety of VEN plus arsenics (arsenic trioxide or oral arsenic drug, realgar-indigo naturalis formula) plus ATRA based salvaged regimen in R/R APL from our center.
Patients and methods: We retrospectively analyzed cases with R/R APL who received VEN plus arsenics and ATRA based regimen at our institution from July 2021 to December 2023. During the reinduction cycle, patients received 0.15 mg/kg/day intravenous infusion of Arsenic trioxide or oral RIF daily 60 mg/kg/day. ATRA was administered 25 mg/m2/day. VEN was administered using a daily ramp-up strategy (100 mg on day 2, 200 mg on day 3, and 400 mg on days 4-28). The last date of follow-up for this analysis was May 2024.
Results: Thirty-one patients with R/R APL were enrolled, 10 patients has co-occurred with CNS relapse, and 1 patient with CNS relapse only. Four patients had ≥ 2 therapies. All patients had prior exposure to arsenics and ATRA. The median age was 44 years (ranges, 18-72).
After once cycle of reinduction, the overall response rate (complete remission/complete remission with incomplete count recovery) was 97% (30 of 31), CR was achieved in 27 patients. No early death was occurred. Side effects were manageable. With the median follow-up of 15 month, the 1-year event-free survival and overall survival rates is 78.7% and 96.7%, respectively.
Conclusions: Our results showed that the combination of VEN plus arsenics and ATRA appeared to be a highly effective therapy option for patients with R/R APL, and underline its potential activity also in patients with CNS involvement.
In Vivo panCAR-Mediated Depletion of B Cells in Non-Human Primates Using a Circular (oRNA®) Anti-CD20 CAR
Authors: Crabtree Juliet , Emmanuel Akinola , Sankaran Ganapathy Subramanian , Dutta-Simmons Jui , Kosakowska Karolina , Dimezzo Tracy , Langer Ian , Vyas Prapti , Soto David , Thakkar Akshi , Chen Grace , Sedic Maja , Barros Scott , Horhota Allen , Dalkilic-Liddle Isin , Thiruneelakantapillai LT , Jayaraman Muthusamy , Hoban Megan , Neumann Frank , Mabry Robert 
Published: December 2024

While traditional ex vivo-generated chimeric antigen receptor (CAR) T cell therapies have had tremendous success in the clinic, manufacturing, safety, and accessibility challenges remain. The prospect of an in vivo CAR therapy without the need for patient cell isolation and culture and the safety risks associated with conditioning regimens remains a therapeutic goal. Orna Therapeutic's panCAR™ combines a synthetic, circular coding RNA platform (oRNA®) and proprietary immunotropic lipid nanoparticle (LNP) to drive CAR expression on the surface of immune effector cells (e.g. T cells, NK cells) after in vivo administration, promising a transient, re-dosable, and scalable immune cell therapy without the need for preconditioning lymphodepletion. Orna's panCAR technology leverages both a high-throughput LNP discovery engine, capable of unlocking LNP-mediated RNA delivery to extra-hepatic tissues, with a proprietary FoRCE platform capable of identifying oRNA-required IRES sequences that initiate protein translation in target cells.
Our lead immunotropic LNP, LNP-6, delivers RNA cargo to 60% of splenic and 84% of peripheral blood T cells in non-human primates (NHP) using a reporter RNA cargo. When paired with an oRNA cargo, LNP-6 demonstrated up to ~70% delivery of an anti-CD20 CAR to NHP T cells and human T cells in vitro, maintaining expression over 72 hours. In cytotoxicity assays, both an anti-CD20 CAR and anti-CD19 CAR construct were able to kill human B lymphoblast cell lines in vitro. Using a humanized mouse model, an LNP-6-delivered anti-CD20 CAR oRNA showed significant B cell depletion in peripheral blood, spleen, and bone marrow at 24 hours (75-80% reduction) and sustained B cell depletion 7 days after dosing in the peripheral blood and bone marrow compartments. In NHPs, LNP-6 delivery of an anti-CD20 CAR oRNA resulted in a 95% reduction in B cells with sustained depletion (82%) 7 days after a single dose. These data support the opportunity for exploration of in vivo CAR therapies in oncologic disease settings.
Classical Hematology: Not so Easy! Call for Expert!
Authors: Thomas Melissa , Gibson Spencer , Moss Arianna S , Quy Ray , Zhao Eva , Wang Angelina , Debeusscher Ben P , Pakbaz Zahra 
Published: December 2024

Background:
Studies have previously shown that the addition of a sickle cell specialist to the management team for patients with Sickle Cell Disease improved health outcomes and healthcare utilization (1). This data analysis evaluates the patient outcome when a classical hematologist is added to the management team for patients with non-cancer blood disorders, given that current projections suggest the demand for adult hematologists will exceed the existing supply in the United States (2).
Methods:
This study is a retrospective chart review of 759 adults (mean age +/SD of 52.5 years +/- 18.4, 447 females) seen between February 2020 and July 2023 in a single-provider non-cancer hematology clinic at an academic center. Data collected included type of referring provider specialty, referral reason or diagnosis, diagnosis made by the classical hematologist, new additional contributing diagnoses, and new unrelated incidental findings discovered during the work up.
Results:
Of the 759 patients seen by the classical hematologist, 356 patients (group A) were referred for management advice or confirmation of the diagnosis, andremainingpatients (group B) were referred seeking a diagnosis. Of note, 18% of the 759 referrals were from another hematologist/oncologist seeking a second opinion. During work up for group A, the diagnosis was changed in 34 patients (9.6%), one or more new contributing causes for their referral reason were discovered in 89 patients (25%) and 80 patients (22.47 %) were found to have one or more new unrelated but clinically significant diagnosis. In 99.26% of patients in group B, a visit to the classical hematologist led to a new diagnosis to address the reason for referral; 55% of patients had only one diagnosis while in remaining patients' the diagnosis was found to be multifactorial. During workup for group B, at least one new incidental but clinically significant finding was discovered in 16% of patients.
Conclusion:
This data demonstrates that adding classical hematologists to the care team improves diagnostic evaluation and management of patients with non-cancer blood disorders and their overall quality of care. The significant number of referrals from hematology/oncology to classical hematologists indicates their value seen from within the field and the clear need for their expertise.
References Deva Sharma, Natalie Wallace, Erik A. Levinsohn, Ariela L. Marshall, Karen Kayoumi, Johanna Madero, Morgan Homer, Robby Reynolds, Janet Hafler, Nikolai A. Podoltsev, Alfred Ian Lee; Trends and factors affecting the US adult hematology workforce: a mixed methods study. Blood Adv 2019; 3 (22): 3550-3561. doi: https://doi.org/10.1182/bloodadvances.2019000307Mainous AG 3rd, Rooks B, Tanner RJ, Carek PJ, Black V, Coates TD. Shared Care for Adults with Sickle Cell Disease: An Analysis of Care from Eight Health Systems. J Clin Med. 2019 Aug 2;8(8):1154. doi: 10.3390/jcm8081154. PMID: 31382365; PMCID: PMC6723540.
IFN1 Blockade Enhances Non-Activated CAR T Cell Anti-Tumor Function Via Inhibiting the Innate Anti-Viral Response
Authors: Durgin Joseph , Kazmi Shadab , Kelly Andre , O'Connor Roddy S. , Ghassemi Saba 
Published: December 2024

Chimeric antigen receptor (CAR) T cells have demonstrated unprecedented success in treating blood-based cancers. However, the durability of response is often hindered by challenges related to long-term T cell persistence and engraftment. The efficacy of CAR T cell immunotherapy relies on the differentiation status and overall fitness of the CAR T cell product. Current protocols involve the activation and ex vivo expansion of patient T cells, however, activation leads to irreversible differentiation, compromising their therapeutic potency.
Manufacturing protocols utilizing non-activated T cells results in superior differentiation characteristics and reduced exhaustion, with concordant benefits in long-term tumor control. Nevertheless, as quiescent T cells are highly resistant to lentiviral infection, CAR T manufacturing yield is a significant limitation with non-activated T cells. In this study, we investigated the impact of IFN1 blockade on CAR lentivirus transduction and function of non-activated T cells.
Quiescent T cells were treated with an IFN1 binding protein, or vehicle, and transduced with CAR19 lentiviral vectors. Our findings demonstrate that lentiviral vector transduction triggers an innate immune response in non-activated T cells, resulting in reduced transduction efficiency, and altered T cell differentiation. Inhibiting the anti-viral response via blockade of IFN1 during transduction promotes a more naïve and central memory phenotype. We further investigate the effect of IFN1 blockade by lentiviral-mediated expression of CAR as well as a secreted IFN1-binding protein. These CAR T cells show enhanced cytolytic activity and cytokine production against target cells after repeated antigen exposure.
We, therefore, tested the effect of IFN1 blockade in a preclinically validated xenograft NALM6 model of leukemia. After establishing xenografts, a suboptimal dose of CART19 (1e6 T cells), generated in the presence of IFN1 binding protein, was infused. These CAR T cells demonstrated enhanced tumor control relative to standard CAR T cells. Our studies in vivo suggest that the sustained secretion of the protein to block IFN1 may enhance the therapeutic activity of T cells in tumors reliant on IFN-mediated immune evasion.
Our results identify a novel approach to enhance non-activated CAR T cell transduction and fitness by countering anti-viral defenses triggered during gene delivery. Mechanistically we show that blocking IFN1 signaling with a binding protein improves transduction and anti-tumor function of non-activated CAR T cells during repeated antigen exposure. Given the therapeutic promise of non-activated CAR T cells, our findings have immediate translational relevance for broadening their appeal against cancer.