bluuebunny/crossref_metadata_2025_split huggingface dataset:
Orally Effective CDK9 Inhibitor YX0798 for Treating Aggressive Lymphoma
Authors: Jiang Vivian , Xue Yu , Kim Hong , Cai Qingsong , Zhang Tianci , Nie Lei , McIntosh Joseph , Liu Yang , Chen Haiyan , Santos David , Thirumurthi Selvi , Zhou Jia , Wang Michael 
Published: December 2024

Introduction
Non-genetic transcription evolution has been increasingly recognized as a contributor to tumor cell progression and therapeutic resistance. Transcriptomic reprogramming and tumor cell progression results from cyclin-dependent kinase 9 (CDK9) dysfunction, with CDK9 as the linchpin of transcription machinery through RNA polymerase II (Pol II) transcription. Our laboratory has recently shown that in mantle cell lymphoma (MCL), the HSP90-MYC-CDK9 network drives transcriptomic reprogramming, resulting in therapy resistance. We also showed AZD4573 and enitociclib are safe and effective treatments in preclinical MCL models, and the therapeutics target CDK9. However, current CDK9 therapeutic candidates could be improved by enhancing target selectivity and oral bioavailability.
Methods
In this study, we showcase a novel CDK9 inhibitor, YX0798, evaluating its potency and safety using preclinical MCL platforms and models. Molecular docking with Schrodinger was used to investigate the interaction of YX0798 with the CDK9 crystal structure. Binding assays with scanMAX were used to determine the selectivity of YX0798 across 468 kinases. Cell viability assays were conducted to assess in vitro efficacy. Apoptosis assays, western blots, and bulk RNA sequencing were used to determine the mechanism of action in MCL cells. Pharmacokinetic and pharmacodynamic profiling was conducted to determine the drug-like potential of YX0798. Patient-derived xenograft (PDX) models were used to determine the therapeutic potential of YX0798.
Results
The novel CDK9 inhibitor YX0798 have high target selectivity and good oral bioavailability. YX0798 demonstrated greater selectivity and greater affinity than commercial competitor in binding to CDK9. When administrated orally (5 mg/kg, daily), YX0798 led to even better anti-tumor activity in MCL resistance PDX models than the commercial competitor with intravenous injection at an equivalent dosing. Mechanistically, YX0798 or the commercial competitor led to CDK9 inhibition and primarily resulted in downregulation of short-lived oncoprotein c-MYC and pro-survival protein MCL-1. Ultimately, CDK9 inhibition disrupted the cell cycle and switched cellular metabolism towards oxidative phosphorylation, eventually leading to cell death.
Conclusions
Together, our study demonstrates that YX0798 is an orally bioavailable CDK9 inhibitor with exquisite selectivity and anti-tumor potency that drives transcription reprogramming towards tumor cell killing.
A Longitudinal Examination of the Quality of Life of Persons with Hemophilia a Switching from Intravenous Recombinant Factor VIII Concentrate to Subcutaneous Non-FVIII Replacement Therapy
Authors: O'Rourke Roxy , Bouskill Vanessa , Wakefield Cindy , Carcao Manuel , Abad Audrey , Blanchette Victor , Malcolmson Caroline 
Published: December 2024

Background. In Canada, ‘standard of care’ for persons with hemophilia A (PWH-A) has been regular intravenous infusions of factor VIII (FVIII) concentrates started early in life. Recently, novel non FVIII therapies that do not require intravenous infusion, and are administered infrequently and subcutaneously, have become clinically available. These therapies may impact health-related quality of life (HR-QoL) of PWH-A. This patient-reported outcome can be assessed using the Canadian Hemophilia Outcomes-Kids Life Assessment Tool (CHO-KLATv3.0).
Aim. To compare the long-term HR-QoL of PWH-A pre-/post-switch to emicizumab.
Methods. PWH-A on FVIII prophylaxis, and their caregivers, completed questionnaires at baseline (day of switch to emicizumab), 3-, 6-, and 12-months post-switch. This study was approved by the institutional research ethics board. Informed consent was obtained from participants. PWH-A aged 7-18 years completed the self-report CHO-KLAT, and caregivers of PWH-A aged 0-18 years completed the caregiver-report CHO-KLAT. The CHO-KLAT is scored 0- 100, with 100 representing best HR-QoL. The CHO-KLAT is also scored within 7 domains: activities, autonomy, bleeding, emotional health, hemophilia knowledge, social functioning, and treatment.
Results. PWH-A (N=26; Mage=12.4 years, SD=4.2; 100% male; 97% infusing prophylaxis &gt;twice/week pre-switch) and their caregivers (N=34) completed the questionnaires. Mean CHO KLAT scores increased at 3-months and plateaued by 12-months. Child and caregiver CHO-KLAT scores were significantly correlated at baseline (ρ=.53**, CI=.16-.77) and 12-months (ρ=.92**, CI=.66-.98), indicating similar caregiver versus child-perceived HR-QoL longitudinally. There was a significant improvement in caregiver-reported CHO-KLAT scores from baseline to 3- months, by an average of 8.65 (t18=-3.36, CI=-14.05–3.25). There was a significant improvement in caregiver-reported autonomy from baseline to 12-months (Z=-3.26, p&lt;.001).
Conclusion. PWH-A and their caregivers reported greatest HR-QoL at 3- and 6-months post switch. The HR-QoL findings align with the literature on other chronic conditions, where the greatest changes are observed immediately following a treatment switch, followed by a plateau over time.
Evaluation of Prognostic Factors Involved in the Evolution of Secondary Acute Leukemia Patients
Authors: Omer Meilin , Popov Viola Maria , Bumbea Horia , Andreescu Mihaela , Bacanu Maria , Popescu Mihaela , Ofiteru Geanina , Mihai Lidia Felicia , Patrinoiu Oana , Dumitru ION , Soare Dan Sebastian , Arghir Aurora , Vladareanu ANA Maria 
Published: December 2024

BACKGROUND
Secondary acute leukemia (sAL) has a worse prognosis, with severe evolution and higher risk of sepsis. Previous chemotherapy could cause genetic mutations that influenced the prognosis of sAL.

OBJECTIVE
To identify prognostic factors in patients with sAL.

METHOD
A retrospective study from 2015-2024 included 109 patients with acute leukemia diagnosed in the Hematology Clinic of the Colentina Clinical Hospital. The study group included 69 patients with secondary acute leukemia: 39 patients with chronic hematologic neoplasms and 30 patients with solid tumors. We enrolled a control group that included 40 patients without neoplasia in their medical history. The analyzed variables were Flow cytometry markers: CD56, CD71, CD 123, CD7, CD9; cytogenetic and molecular markers, hematological and biochemical parameters.

RESULT
Aberrant expression of CD56, CD7, CD9, CD71 and CD123 influenced the survival of patients with sAL, the chi-squared of overall model fit is 13.61, p=0.01. The most important marker is CD71 expression, the median survival in the patient group is 3 months (95% for median-1-9 months) vs 14 months (95%Ci for median-5-60 months) in the control group, p = 0.0006. We obtained no significant differences in cytogenetic or molecular marker for survival analyses. Patients with sAL followed by solid tumor have more blasts in the bone marrow than patients with chronic hematological neoplasms with a median value 43% , average rank =19.63 vs 75% average rank= 28.5, p=0.02. The severity of neutropenia is more important in patients with sAl with solid tumor in their history than in patients with chronic hematologic neoplasia, with a median value 1.15, average rank 28,96 vs 2.72 average rank =37,61, p=0, 05. Probably because of neutropenia, patients with solid tumors have higher values of C-reactive protein (CRP) and fibrinogen and more frequent severe infections that influenced the evolution of patients.

CONCLUSIONS
Patients with solid tumor in the medical history have an aggressive form of acute leukemia at onset represented by severe neutropenia and with higher frequency of inflammatory markers, higher rate of bone marrow blasts. The presence of CD71, CD56, Cd7, CD9 and CD 123 expression could indicate the worst evolution of sAL patients.
Genome-Wide Association Study of Chronic Pain in Sickle Cell Disease
Authors: Sowa Anna , Hu Yue , Gladwin Mark T. , Gordeuk Victor R. , Nouraie Seyed Mehdi , Zhang Yingze , Pashankar Farzana D. , Krishnamurti Lakshmanan , Gruen Jeffrey 
Published: December 2024

Background:
For many patients with sickle cell disease (SCD), episodes of acute pain occur within the context of debilitating persistent or chronic pain. Over half of adult patients report pain on more than half of the days, and almost a third experience pain on 95% of days. No previous GWAS studies have explored the association of genetic polymorphisms with chronic pain in SCD.
Methods:
We conducted a genome-wide association study (GWAS) involving 405 SCD patients using data from the screening phase of the Walk-PHaSST study (NCT00492531). Participants were age 12 years and older, with a median age of 35 years, and 53% were female; 73% had hemoglobin (Hb) SS, 18% had Hb SC, 4.0% had Hb Sβ + thalassemia, and 4.9% had other subtypes of SCD. Genotypic data were filtered to exclude SNPs with a call rate below 95%, deviations from Hardy-Weinberg equilibrium (P &lt; 0.00001), or a minor allele frequency under 0.05, resulting in 9,874,538 SNPs for analysis. We performed a proportional odds logistic regression to evaluate the association between SNPs and self-reported chronic pain levels, rated on a 0 to 10 scale. Adjustments were made for age, sex, SCD subtype, alpha-thalassemia, hemoglobin concentration, hydroxyurea usage, and the first 10 principal components to control for population stratification.
Results:
Chronic pain was reported by 146 patients (36%). Three SNPs reached genome-wide significance: rs8026638 (p = 4.16 × 10^-8), rs7180285 (p = 4.64 × 10^-8), and rs10152723 (p = 4.96 × 10^-8). These SNPs, all in high linkage disequilibrium, are located on chromosome 15 within the intronic region of the CHD2 (Chromodomain Helicase DNA Binding Protein 2) gene.
Conclusions:
To the best of our knowledge, this is the first GWAS to identify a locus for chronic pain in SCD that exceeds genome-wide significance threshold. Analyzing a small but well-phenotyped cohort of individuals with SCD, we found association with three SNPs within the CHD2 gene. The CHD2 gene, part of a family of genes that modify chromatin structure to alter gene expression, has previously been associated with cognitive function, generalized myoclonic and atypical absence seizures, and abnormal pyramidal signs. Further validation in larger cohorts and additional biological studies are needed to confirm these associations and to further explore their potential modulating effects on pain pathophysiology and perception.
Variability in Internal Algorithms for Sickle Cell Disease
Authors: Quraishi Mariam z , Menon Neethu M , Yadav Aravind , Srivaths Lakshmi V , Brown Deborah L , Okeleji Olayinka , Elgehiny Amr 
Published: December 2024

Background:
While national guidelines for the management of vaso-occlusive crisis (VOC) and acute chest syndrome (ACS) in sickle cell disease (SCD) exist, institutional algorithms are tailored to their clinical practices. This study aims to compare institutional algorithms to each other and to national recommendations for VOC/ACS in pediatric SCD.
Methods:
Algorithms were collected from children's hospitals across the United States and compared to recommendations made by the National Heart, Lung, and Blood Institute (NHLBI) 2014 and the American Society of Hematology (ASH) 2020 regarding management of VOC/ACS in SCD.
Results:
Review of 37 VOC and 17 ACS algorithms from 40 children's hospitals showed that most followed national guidelines for diagnostic evaluation of VOC/ACS. Parenteral opioids and NSAIDs were recommended by all VOC algorithms, with variations in dosing and administration. Intranasal fentanyl was recommended by 31 algorithms, with individualized pain protocol and non-pharmacological measures mentioned in 19 each. Incentive spirometry was included in 16 of 17 ACS algorithms, but only 11 of 37 VOC algorithms. Antibiotics were recommended by all ACS algorithms, but 4 used regimens different from the NHLBI recommendation. Most ACS algorithms had recommendations regarding transfusion, but with considerable variability. Exchange transfusion guidelines from either NHLBI or ASH were included in 14 of 17 ACS algorithms. Intravenous fluid management strategies were highly variable and hypotonic fluids were recommended in 6 VOC and 4 ACS algorithms.
Discussion:
This study is the first of its kind to review algorithms across the country regarding VOC and ACS management in children. Institutional algorithms generally aligned with national guidelines for management of VOC and ACS, but significant treatment variations were observed. Many algorithms did not include certain recommendations specified in the national guidelines, such as incentive spirometry, despite its widespread availability and effectiveness. Intranasal fentanyl (INF) was commonly recommended in VOC algorithms, aligning with its proven efficacy as an opioid analgesic. Variability in IVF recommendations likely stems from the lack of randomized controlled trials addressing IVF benefits and risks in VOC and ACS. Variations existed in transfusion indications in ACS, possibly due to ambiguity in definitions of severity of ACS in national guidelines. Despite technical challenges, most protocols recommended exchange transfusion for severe ACS, in line with national guidelines.
Conclusion:
Despite the presence of national guidelines, internal algorithms for VOC and ACS in pediatric SCD show great variability, likely due to the lack of robust evidence supporting specific recommendations in national guidelines. Prospective studies are crucial to fill these evidence gaps with the overall goal of improving patient care.
Adaptive, Rapid, Parallel-Phase Implementation of the Chemopad to Combat Substandard/Falsified (SF) Chemotherapy Drugs across Sub-Saharan Africa
Authors: Gomes Suzan , Stillwell Anna , Ippolito Elise , Lieberman Marya , Muluneh Benyam 
Published: December 2024

Background: In low- and middle-income countries (LMICs), a significant proportion of medications, including anticancer agents, are substandard or falsified (SF).1 These poor-quality medicines do not meet the necessary specifications for standard, appropriate patient care.1 The prevalence of SF chemotherapy drugs compromises treatment efficacy and patient safety, increasing the risk of morbidity and mortality and loss of rapport in the healthcare system.2 To safeguard public health, the ChemoPAD, a low-cost paper analytical device, was developed to detect the presence of active pharmaceutical ingredients (APIs) and identify potential SF chemotherapy medications in LMICs.3
Methods: This study methodology was guided by implementation mapping and consisted of a parallel, adaptive approach of two phases - pre-implementation and clinical implementation.4 The pre-implementation involved a collaboration with Tikur Anbessa Specialized Hospital (TASH), Moi Teaching and Referral Hospital (MTRH), and Kamuzu Central Hospital (KCH) - National Cancer Center, to conduct an implementation needs assessment through three virtual informal focus groups. The participants (n = 8) were pharmacists, pharmaceutical coordinators, and the heads of the pharmacy department. The discussion was guided by workflow mapping questions using the CFIR framework. A data trend analysis compared current workflow processes, ChemoPAD feasibility, and barriers and facilitators for implementation. In parallel, a nominal group technique was employed to facilitate discussions on exploring and refining program objectives and implementation strategies with the ChemoPAD research team (n = 14) for the clinical implementation phase.5 This iterative approach facilitated consensus and generated ideas, which were further refined through focus groups before reintroduction to the research team for additional feedback and consensus-building.
Results: Both phases discovered ways to promote sustainable workflows. In the pre-implementation phase, participants were receptive to incorporating the ChemoPAD into the workflow, favoring a proactive screening approach for hospital-supplied chemotherapy medicines to ensure drug quality, reduce the risk of adverse events, and prevent supply chain disruptions. Barriers and facilitators have been identified and will be considered for successful ChemoPAD implementation. In the clinical implementation phase, concrete strategies developed include: standard operating procedure, training materials, workflow diagrams, and designating hospital staff and regulatory champions.
Conclusions: This study demonstrated the use of a rapid, adaptive, parallel-phase implementation approach and virtual communication methods to enhance implementation science research in multiple LMIC settings.
Novel Instrument for Measuring Oxygen-Equilibrium Curve
Authors: Aprelev Alex , Pochron Mira , Gaputan Polo , Shestakov Olek 
Published: December 2024

Introduction: Hemoglobin plays a crucial role in the delivery of oxygen from the lungs to the body's tissues. The binding function of hemoglobin can be directly measured by simultaneously assessing both the oxygen pressure and saturation level of hemoglobin while changing the oxygen content from zero to a reasonable maximum, then back to zero. The curve describing the dependence of hemoglobin saturation as a function of oxygen pressure is called the Oxygen Equilibrium Curve (OEC). The characteristic point of the OEC curve is the oxygen pressure corresponding to 50% saturation of hemoglobin (P50).
Current instruments capable of measuring OEC have a variety of limitations that have thus far limited the wider applications for OEC measurements in pharmacological and medical applications. This includes large blood sample sizes, complex consumables, and lengthy test procedures.
Aim: The goal of our current development is to suggest a novel method for improved measurement of P50 and the OEC curve.
Methods: OxyDial's OEC measurement methodology prioritizes improvements in four key areas when compared to currently-available instruments: Full spectrum absorption spectroscopy is used to measure hemoglobin saturation. This increases measurement precision and enables the detection of Met-Hemoglobin.Oxygen pressure is measured using the lifetime of phosphorescent dye. This simplifies the instrument and negates the need for calibrations which would otherwise be required.An enzymatic reaction is used to reduce oxygen pressure from atmospheric levels to zero. This decreases the required sample volume to 10uL, and avoids the need for gas cylinders.Samples are contained in a small glass capillary (similar to a micro-hematocrit capillary), ensuring contamination-free cleaning and operation, as the only component in direct contact with blood is the disposable capillary itself. Capillary temperature can be precisely controlled to a level of 10mC.
Results: The suggested method provides significant improvements compared to methods used in the older instruments, which are limited to 2 wavelengths, and necessitates the use of Clark's electrodes, a 1 cm optical cuvette with a stirrer, and a defoaming agent. In contrast, OxyDial's novel OEC method and instrumentation have been proven to provide more reliable and precise operation and require no significant service or deployments. A single OxyDial OEC instrument could conduct 30 full tests in a day, with the simple operation allowing a single operator to run up to 4 instruments simultaneously.
Conclusion(s): We recommend switching from the older OEC testing methods to novel OxyDial OEC testing methods.
Heme Oxygenase-1 Regulates the Hepatic Expression of Hemoglobin Scavenger Receptor CD163 in Sickle Cell Disease
Authors: Mozhenkova Anna , Pradhan-Sundd Tirthadipa 
Published: December 2024

Sickle cell disease (SCD) is the result of a genetic mutation in the β-globin gene, where both copies of the gene are affected. This mutation causes red blood cells to change shape into a sickle shape, leading to their premature destruction and the release of hemoglobin. Plasma haptoglobin scavenges cell free hemoglobin (Hb) and escorts it to the liver, where it is cleared by macrophages (specifically hepatic Kupffer cells) through a process that depends on the hemoglobin scavenger receptor CD163. Nevertheless, the persistent breakdown of red blood cells in SCD causes a decrease in plasma haptoglobin levels, which in turn leads to the buildup of hemoglobin, heme, and iron, leading to multi organ damage including liver damage. Past investigations have demonstrated a limited number of instances where there is a positive relationship between CD163 expression and unfavorable clinical outcomes in patients with SCD. However, the precise function and control of CD163 in regulating hepatobiliary damage in SCD have not yet been completely understood.
The objective of this study was to examine the function of CD163 as a potential biomarker for the severity of liver damage associated with SCD. This was done by utilizing a humanized mice model and liver biopsy samples obtained from SCD patients. We found that there is a positive correlation between chronic liver damage in mice and individuals with sickle cell disease (SCD) and increased levels of hepatic membrane bound CD163. Mechanistically we show that heme oxygenase 1 (HO-1) is a positive regulator of CD163 in the liver of SCD mice, independent of the nuclear factor erythroid 2-related factor 2 (NRF2) signaling. Additional investigation revealed that toll-like receptors (TLRs) 4 and 9 interact with both CD163 and HO-1 and control the regulation of membrane bound CD163 in SCD mice liver. Finally, we demonstrate that the reduced activity of CD163 exacerbates liver damage caused by hemolysis in sickle cell disease (SCD) as a result of the accumulation of hemoglobin specifically in the liver.
This study finds CD163 as a possible indicator of liver damage caused by hemolysis in SCD. A comprehensive comprehension of the HO-1 mediated signaling pathways that regulate CD163 expression will prove valuable in the development of innovative treatment strategies for addressing tissue damage caused by hemolysis in SCD and other hemolytic diseases.