bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and Safety Profile of CPX-351 in Secondary Acute Myeloid Leukemia (sAML): A Systematic Review
Authors: Ibrahim Ahmed , Yousaf Muhammad Abdullah , Ikram Mariam , Khalid Huma , Anum . , A Safdar Omar , Anwer Zain , Faraz Fatima , Rehman Mohammad , Saad Muhammad 
Published: December 2023

Secondary Acute Myeloid Leukemia (sAML) is a subgroup of Acute Myeloid Leukemia (AML) associated with poor outcomes despite recent advancements in chemotherapy. CPX-351 (United States: Vyxeos®), a 1:5 liposomal encapsulation of daunorubicin and cytarabine was approved in 2017 by the US Food and Drug Administration (FDA) for the treatment of newly diagnosed Secondary AML. Previously, the conventional 7+3 Regimen (7 days of cytarabine and 3 days of daunorubicin) was considered first line for the treatment of sAML. However, the pivotal study that led to approval of CPX-351 demonstrated increased Overall Survival (OS) with CPX-351. We report a systematic review of published literature on the efficacy and safety of CPX-351 in patients with sAML, including data from post-market real-world experiences of patients.
Materials and Methods Following PRISMA guidelines, we performed a comprehensive literature search for articles published after 2017 using PubMed, Embase, Clinical Trials.gov, Cochrane Library, and Web of Science. Initially 63 articles were identified, and after a thorough screening, we finalized 9 studies including 767 patients, illustrated in Table 1. We analyzed data from patients who received CPX-351 chemotherapy as first-line therapy for sAML. MeSH terms and keywords were 'CPX-351' and 'Leukemia, Myeloid, and Acute'.
Results The median age of patients was 65.9 years. Patients could receive up to two cycles of induction, and those who achieved complete remission (CR) or complete remission with incomplete recovery (CRi) could receive up to 2 cycles of consolidation with CPX-351. CPX-351 treatment showed median overall survival (mOS) of 12.20 months, CR rate of 43.66%, and an overall remission rate (ORR) of 51.1%. Hematopoietic Stem Cell Transplantation (HSCT) was performed in 39.1% patients. The mean time to absolute neutrophil count &gt;500/mL (mANC) and platelet count &gt;50,000/mL (mPC) recovery in patients who achieved OR was 34.4 days and 32.9 days, respectively. The most frequently reported greater than grade 2 adverse events (AEs) were febrile neutropenia (NF), opportunistic infections including pneumonia, and hypoxia.
Conclusion In sAML patients, the CPX-351 regimen is more effective and well tolerated as compared to the conventional 7+3 Regimen. The real-world data also points to CPX-351 as an efficient therapeutic agent for sAML patients facilitating HSCT in many patients with promising outcomes after transplantation. CPX-351 is a treatment of choice for patients aged &gt;60 years. Future randomized prospective trials with longer follow-up periods are needed to consolidate these findings, and help us better understand the efficacy and survival outcomes of CPX351 regimens for sAML treatment.
Preclinical and Early Clinical Results Indicate a Role for the Oral p300/CBP Inhibitor Inobrodib (CCS1477) in T-Cell Lymphoma
Authors: Campbell Victoria , Walter Harriet , Gibb Adam , Davies Andrew S. , Elmusharaf Nagah , Pegg Neil , West Will Henry , Knurowski Tomasz , Frese Kris , Haynes Debbie , Clegg Karen , Somervaille Tim 
Published: December 2023

Inobrodib (CCS1477) is a potent, selective, and orally bioavailable inhibitor of the bromodomains of CBP and EP300, two homologous histone acetyltransferases with critical roles in cellular growth and differentiation. Lymphomas can harbor multiple putative predictive biomarkers for inobrodib, including deleterious mutations in CBP/EP300 that convey synthetic lethality and expression of the lineage transcription factors IRF4 and GATA3.
The preclinical efficacy of inobrodib was assessed in a range of solid cancer and hematological cancer cell lines. Select models, including multiple myeloma, acute myeloid leukaemia, and lymphoma cell lines were sensitive to submicromolar concentrations of inobrodib. These in vitro results were extended to xenograft models in which inobrodib demonstrated dose-dependent efficacy.
Based on these results, we initiated a clinical trial to test the safety and efficacy of inobrodib in advanced hematological malignancies (NCT04068597). Dose escalation was conducted in multiple myeloma patients and select B and T-cell lymphomas. The safety profile was similar to other hematological and solid tumour indications with readily manageable and reversible thrombocytopenia as the main toxicity. The recommended phase 2 dose was established at 35mg bidaily on a 4 days on/3 days off intermittent schedule.
Initial data in peripheral T cell lymphoma - not otherwise specified (PTCL-NOS) shows a potential benefit with objective responses in 3 of 4 patients as of data cut-off date (20 Jul 2023). These included a complete metabolic response in a patient (with previously refractory disease) continuing on treatment for over 1.5 yrs and 2 patients with minor responses. Translational investigations indicate that responders all express IRF4 and GATA3, but do not harbour CBP/EP300 mutations.
Together these data support the further development of inobrodib for the treatment of peripheral T cell lymphoma. Expansion continues with a focus on T-cell lymphomas, which may be driven by IRF4 and GATA3.
Outcomes Among Hospitalized Patients with Acute Chest Syndrome and Concomitant Clinical Depression: A United States Population-Based Cohort Study
Authors: Syal Arshi , Arya Yajur , Casipit Bruce Adrian , Dourado Claudia , Mayo Ryan J , Casipit Carlo 
Published: December 2023

Background
Acute chest syndrome is a life-threatening complication of sickle cell disease, seen in both children and adults. Hospitalization and immediate treatment are necessary to prevent morbidity and mortality. Clinical depression is quite prevalent in patients with sickle cell disease, and review of literature reveals association of depression with increased annual emergency department visits, hospitalizations, and blood transfusions in patients with sickle cell disease. Whether this leads to worse outcomes is yet to be ascertained.
Methods
We utilized the 2018-2020 National Inpatient Sample (NIS) Database in conducting a retrospective cohort study. We identified hospitalized patients with acute chest syndrome and concomitant clinical depression using appropriate ICD-10 CM codes. We stratified patients based on whether they had clinical depression during the hospitalization or not. A survey multivariable logistic and linear regression analysis was used to calculate adjusted odds ratios (OR) for the primary and secondary outcomes. A p value of &lt;0.05 was considered statistically significant. The aim of this study is to investigate the outcomes among hospitalized patients with acute chest syndrome and comorbid clinical depression looking primarily at the in-hospital mortality and hospital length of stay (LOS).
Results
We identified a total of 5271 hospitalized patients with acute chest syndrome, of which 10.72% (565/5271) had comorbid clinical depression. The overall in-hospital mortality among those with acute chest syndrome was 3.70% (195/5271). Among those with clinical depression, the overall in-hospital mortality rate was not significantly higher at 5.31% (30/565) (p=0.385). Utilizing a stepwise survey multivariable logistic regression model that adjusted for patient and hospital level confounders, clinical depression among hospitalized patients with acute chest syndrome did not significantly increase the risk for in-hospital mortality (adjusted OR 1.39, 95% confidence interval [CI], 0.49-3.91; p=0.533) or prolong hospital LOS (median LOS 6 days versus 7 days, p=0.631)
Conclusion
Acute chest syndrome continues to be an important cause of hospital admissions in patients with sickle cell disease. Our analysis revealed that clinical depression is commonly encountered in this subset of patients. Clinical depression did not have a statistically significant impact on outcomes including increased in-hospital mortality or prolonged hospital LOS. Prospective studies with large sample sizes are needed to better understand these outcomes.
Identifying Inflammatory and Immune Markers Associated with Vasoocclusive Crisis in Patients with Sickle Cell Disease
Authors: Li Wei , Pucka Andrew , Debats Candice , Reyes Brandon , O'Brien Andrew Ross Wickman , Yu Qigui , Wang Ying 
Published: December 2023

Background: Sickle cell disease (SCD) is an inherited disorder that can cause a range of clinical complications, featured by unpredictable and recurrent acute painful episodes associated with vasoocclusive crises (VOCs). Individuals with SCD experience frequent VOCs and require high doses of opioids for pain control. Thus far, studies on biomarkers associated with VOCs in SCD are very limited and the known markers are hardly considered as critical end points in studying VOCs in SCD. This study aimed to comprehensively analyze immune and inflammatory characteristics of patients with SCD to understand the disease-specific pathogenesis and develop targeted diagnostic and therapeutic strategies related to VOCs.
Methods: The study cohort consisted of 40 patients with SCD aged 14-73 years (23 female, 58%), recruited for an ongoing clinical trial (ClinicalTrials.gov Identifier: NCT05045820). Twenty-three ethnicity-, age- and gender-matched pain-free participants were also enrolled as healthy controls (HCs) (Table 1). Multiplex immunoassays were used to profile 80 inflammatory cytokines/chemokines/growth factors and 18 autoantibodies in plasma samples from patients with SCD and the matched HCs. Peripheral blood mononuclear cells were used to profile immune cells. Statistical analysis was performed using GraphPad Prism with Mann-Whitney test, χ 2 test, and Spearman's correlation. P &lt; 0.05 was considered statistically significant.
Results: Patients with SCD exhibited significantly higher plasma levels of 34 analytes, including 12 pro-inflammatory/anti-inflammatory cytokines (IFN-γ, IL-1α, IL-2, IL-8, IL-9, IL-18, TNF-α, TNF-β, IL-4, IL-5, IL-6, and TSLP), 10 chemokines (CCL21, CCL23, Eotaxin-2, Gal-3, GRO-α, IP-10, MCP-2, MIP-1α, MIP-1β, and MIP-3α), 8 growth factors (bNGF, G-CSF, GM-CSF, HGF, IL-7, IL-20, IL-34, and LIF), 2 effectors (granzymes A and B), and 2 soluble receptors (PTX3, TREM-1). Higher activation levels of B cells, CD4 T cells, CD8 T cells, and MAIT cells were seen in patients with SCD. Autoantibody profiles were also altered in patients with SCD, with elevated levels of antibodies against SSA/Ro60, Ribosomal P, Myeloperoxidase, and PM/Scl-100. Levels of cytokines/chemokines/growth factors were correlated with time interval between blood draw and occurrence of VOCs. Four soluble factors (Eotaxin-2, GRO-α, IL-6, and LIF) were positively associated with time interval after VOCs, while two factors (IL-18 and granzyme A) showed negative associations with time interval, suggesting that the altered inflammatory mediators were associated with the occurrence of VOC events.
Conclusion: Our results provide novel and comprehensive understanding of the immune and inflammatory dysregulation in patients with SCD and their relationship with occurrence of VOCs, offering insights into potential SCD-specific biomarkers for further investigation.
Exploring the Utility and Significance of an Adult Academic Non-Cancer Hematology Clinic
Authors: Thomas Melissa , Gibson Spencer , Quy Ray , Pakbaz Zahra 
Published: December 2023

Background:
Current projections suggest that the demand for adult hematologists will exceed the existing supply in the United States. Despite this, academic centers' hiring practices and fellows' future career choices appear to place an emphasis on oncology over non-cancer hematology.
Objective:
The primary objective of this study was to assess the overall utility and importance of a clinic dedicated to non-cancer blood disorders within a single academic center by analyzing referral characteristics and select patient demographics.
Methods:
This study is a retrospective chart review of 755 adults seen in a new single-provider clinic for adults with non-cancer blood disorders within the division of hematology oncology at an academic center between February 2020 and July 2023. This clinic was telemedicine only (video visit or phone visit) between February 2020 and August 2022, after which the clinic switched to a hybrid format. Data analysis included specialty of referring provider, reason for referral, and patient demographics including age, sex, and geographic location. Financial returns for the clinic in the fiscal years 2020-2023 were also analyzed.
Results:
Of the 755 patients analyzed, 318 were male and 437 were female, with a median age of 53 years (minimum 17 years and maximum 100 years). Referred patients were from 209 unique zip codes in 92 unique cities with a catchment radius of 340 miles to the north and south, and 94.5 miles to the east and west. One third of referrals were from outside of the UCI Health system. Of the 31 referring specialties, Family Medicine (21.25 %), Internal Medicine (18.19 %), and Hem Onc (17.75%) were the top referrers. The most common reason for referrals were anemia (30.58%), cytopenia (23.23%), and thrombosis/hemostasis (including pre-op clearance) (22.32%). The productivity averaged over the last 3 years the clinic was open was 40% above the defined clinic operation target benchmark. The top 3 common health insurances for the fiscal year 22-23 were managed care (33.78%), Medicare (31.65%), and commercial contracted (28.12%).
Conclusion:
This data analysis demonstrates the growing need for adult hematologists with expertise in non-cancer blood disorders and the high utility and financial revenue potential for non-cancer hematology clinics. Given the vast catchment area of patients being seen, the expertise necessary in the diagnosis and management of non-cancer blood disorders truly shows its value. Furthermore, with such a sizable proportion of referrals originating from other hematology/oncology doctors (3rd highest volume of referrals), it can be inferred that a 2nd opinion from a benign hematologist is valued by those in the field as critical in the diagnosis and management of their patients.
Defining Hereditary Pyropoikilocytosis (HPP) in the Molecular Diagnostic Era
Authors: Jamalapur Sri Lakshmi (Sindura) , Gadgeel Manisha , Ozgonenel Bulent , Ravindranath Yaddanapudi 
Published: December 2023

Misconceptions continue in distinguishing hereditary elliptocytosis (HE) with hemolysis in early perinatal period and hereditary pyropoikilocytosis (HPP). In 1975, Zarkowsky and colleagues described a group of children with transfusion dependent congenital hemolytic anemia with the unique morphology of “microspherocytes, measuring 2-3 microns in diameter, and cells with blunted projections or triangular in shape”, a morphology resembling the heat induced damage to normal erythrocytes - hence the name hereditary pyropoikilocytosis (HPP). Subsequently, similar cases were described with or without demonstrable heat sensitivity (Ravindranath & Johnson, 1985). Regardless, the common denominators were 1) transfusion dependency early in infancy - resolved with splenectomy, 2) severe microcytosis, often &lt;60 fL, and 3) a decrease in membrane bound spectrin (decreased spectrin/band3 ratio). Family studies showed normal RBC morphology in both parents (Ravindranath & Johnson, 1985) or in some cases, one parent with HE (Zarkowsky et al., 1975). Protein chemistry studies showed decreased tetramer formation and tryptic digests showed mutations within the n-terminal alpha 1 domain of alpha spectrin - the dimer/dimer interaction site. Thus, homozygosity or double heterozygosity of mutations in the dimer/dimer interaction site of alpha spectrin (alpha 1 domain of alpha spectrin) defined HPP while classical HE cases showed heterozygous mutations in the alpha 1 domain. A fact unexplained was how this results in spectrin deficiency, specifically, alpha spectrin deficiency (Ravindranath & Johnson, 1985).
Using the molecular analytical tool AnemiaID (courtesy of Agios Pharmaceuticals, Inc.), we show that HPP is defined by the co-inheritance of two SPTA1 mutations and Alpha-LeLy polymorphism ( αLeLy rs28525570; SPTA1[c.5572C&gt;G;c.6531-12C&gt;T]) in one or both alleles, thus explaining the increased propensity for red cell fragmentation and the spectrin deficiency noted on acrylamide gels [Table: Clinical and molecular characteristics of our cases]. Of note, homozygosity for αLeLy polymorphism and one SPTA1 variant did not result in clinical HPP phenotype [HE-2 in Table]. At a clinical laboratory level, the extreme microcytosis in HPP is evident in the markedly diminished band3 content on eosin-5'-maleimide (EMA) binding test- mean channel fluorescence (MCF) of &lt;275.0 (control: 473.0-549.0) while HE (including neonatal HE with hemolysis) show a double peak pattern in EMA (the minor peak representing the fragmented cells while the major peak had MCF higher than control MCF) and the characteristic trapezoid pattern on osmotic gradient ektacytometry (not shown).
Suppression of Microtubule Acetylation Mediates Theanti-Leukemic Effect of CDK9 Inhibition
Authors: Xie Xi , Ren Ruibao , Zhang Bao yuan , Liu Ping 
Published: December 2023

Suppression of Microtubule Acetylation Mediates the Anti-Leukemic Effect of CDK9 Inhibition
Xi Xie1, BaoyuanZhang1, Ping Liu1, Ruibao Ren1,2
1. Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine at Shanghai, International Center for Aging and Cancer, Collaborative Innovation Center of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2. International Center for Aging and Cancer, Hainan Medical University, Haikou, Hainan Province, China.
Cyclin-dependent kinase 9 (CDK9) is a crucial component of transcription and potential target for anti-cancer therapies, particularly for hematological malignancies. However, the precise mechanisms underlying the therapeutic effects of CDK9 inhibitors remain not fully understood. Here, we found that inhibiting CDK9 either pharmacologically or through gene downregulation, significantly reduced the levels of α-tubulin protein in a time- and dose-dependent manner. We further discovered that CDK9 inhibition led to increased susceptibility of α-tubulin to proteasomal degradation due to reduced acetylation at lysine 40 (K40), an important modification for microtubule stability. An acetylation-mimicking mutant of α-tubulin mitigated the anti-tumor effects of CDK9 inhibition. Mechanically, we identified that CDK9 inhibition downregulated the expression of ATAT1, the acetyltransferase responsible for α-tubulin acetylation, further compromising microtubule stability. Our study unravels a novel molecular mechanism by which CDK9 inhibition disrupts α-tubulin stability and provides valuable insights for exploring effective treatment regimens involving CDK9 inhibitors.
Transducing Force into Procoagulation: PIEZO1-TMEM16F Functional Coupling in Blood Lining Cells
Authors: Shan Ke Zoe , Liang Pengfei , Zhang Yang , Yang Huanghe 
Published: December 2023

Thrombosis is a major global disease burden that accounts for 1 in 4 deaths worldwide. Hypertension and preeclampsia greatly increase thrombotic risks by imposing high blood pressure and abnormal hemodynamic shear stress on blood-lining cells, namely endothelial cells (ECs) and placental syncytiotrophoblasts (STBs) in pregnant women. Nonetheless, it remains elusive how abnormal mechanical forces under hypertensive conditions promote coagulation. PIEZO1 mechanosensitive ion channel is a major force sensor in a wide variety of cells, including red blood cells (RBCs) and endothelial cells (ECs), where it transduces mechanical forces into chemical signals through its ion permeability to calcium. On the other hand, TMEM16F is a calcium-activated lipid scramblase (CaPLSase) that translocates phosphatidylserine (PS), an important procoagulant factor, to the cell surfaces of blood cells and endothelial cells. We recently discovered that TMEM16F is the sole CaPLSase in placental trophoblasts and RBCs. Our preliminary results show that PIEZO1 and TMEM16F are functionally coupled in RBCs, and calcium entry through PIEZO1 activates TMEM16F, leading to PS exposure. Based on all these, we hypothesize that in the blood lining cells, PIEZO1-TMEM16F coupling is responsible for transducing mechanical forces into PS exposure, a critical procoagulant signal for blood coagulation.
By employing immunostaining, patch clamp electrophysiology, and a fluorescence microscopy-based scrambling assay, we show that PIEZO1 is functionally expressed in placental trophoblasts, including STBs. We further demonstrate that PIEZO1 activation, either stimulated by its agonist Yoda1 or by shear stress, induces PS exposure in BeWo human trophoblast cell line and human umbilical vein endothelial cell line (HUVEC) but not the TMEM16F deficient cell lines. In addition, using chromogenic tenase and prothrombinase, and fluorescence fibrin assays, we show that PIEZO1 activation by its agonist, Yoda1, triggered coagulation activities in a TMEM16F-dependent fashion in trophoblasts. Our study thus discovers the functional expression of the PIEZO1 mechanosensitive channel in placental trophoblasts and elucidates a novel force-induced procoagulant mechanism in blood-lining cells. In this mechanism, PIEZO1-TMEM16F coupling transduces mechanical forces into procoagulant PS exposure on the blood lining cells. Enhanced PIEZO1-TMEM16F coupling may contribute to hypercoagulable states in hypertension and preeclampsia, and breaking the coupling is therefore a potential therapeutic strategy to prevent thrombotic risks associated with these diseases.