bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Concordance between Laboratory and POCT INR and the Value of Bedside Measurement of INR in Patients on Warfarin Undergoing Dental Procedures: A Prospective Cohort Study
Authors: Albarkheel Abdullah , Owaidah Tarek M , Tamim Hani , Alahmadi Abdullah , Sheikh Aamir , Mushtaq Ali 
Published: December 2023

Introduction: Patients on anticoagulation particularly warfarin suffers when they have a dental problem that requires intervention. Most of dentists worry and refuse to perform procedures on patients on warfarin because of the risk of bleeding and request the availability of international normalized ratio (INR) results before procedure which can delay the procedure and add another burden on the patient particularly who live away from the treating center.
Objective: To evaluate the efficacy and the value of using point of care testing (POCT) (INR) in patients on warfarin undergoing dental procedures. We also had analyzed the frequency and severity of dental bleeding in patients on warfarin therapy and the concordance between Laboratory based INR and POCT INR. This is the first interim analysis on ongoing prospective study.
Methods: A cohort study of 30 patients on chronic use of anticoagulation therapy with warfarin for different clinical indications who planned to undergo dental procedures at a teaching hospital in Saudi Arabia. The patients' demographic and clinical characteristics, type and severity of bleeding, and INR measured by both HemoChrone (POCT) and prothrombin time (PT) were performed at same time. Descriptive statistics, paired samples statistics, correlations, and analysis of variance (ANOVA) were performed.
Results: The sample consisted of 60% females, with a mean age of 49.9 (SD 13.3) years. The most common indications for warfarin therapy were mechanical aortic valve replacement (56.7%), atrial fibrillation (13.3%), and atrial flutter (16.7%). Before the procedure, the mean Laboratory INR was 2.6 (SD 0.6) and the mean HemoChrone POCT INR was 2.8 (SD 0.8). There was a significant positive correlation between the two methods (r = 0.81, p &lt; 0.001). There was no significant difference in the INR and type of bleeding, dentist performed the procedure, or dose of warfarin. There was no correlation between the Bleeding severity or type and the INR level in patients undergoing different dental procedures. Even among those with HemoChrone POCT INR &gt; 3, which is considered high and increases the risk of bleeding, there was no significant correlation with bleeding.
Conclusion: These results imply that warfarin therapy can be safely continued for most dental procedures without increasing the risk of bleeding regardless of the INR results. The HemoChrone POCT INR is a dependable and practical method to monitor the effect of warfarin in dental settings which can reassure the dentists before procedure.
Figure 1: The concordance between Laboratory and POCT INR
BOD1L Facilitates Chromatin Binding of SETD1A and Promotes Leukemia Cell Growth
Authors: Hoshii Takayuki , Kikuchi Sota , Shibata Seito , Matsumoto Makoto , Rahmutulla Bahityar , Fukuyo Masaki , Armstrong Scott A , Kaneda Atsushi 
Published: December 2023

The H3K4 methyltransferase SETD1A plays an essential role in leukemia through a non-catalytic activity which regulates transcriptional pause release of RNA polymerase II. SETD1A localizes to the transcriptional start site of numerous actively transcribed genes, but primarily regulates the expression of a restricted set of genes within the DNA damage response as well as heme biosynthesis pathway. However, the roles of upstream regulators or essential components of SETD1A chromatin binding remain unclear.
Using the DepMap database and a CRISPR-tiling screen method, we found that BOD1L is the most correlated co-dependency with SETD1A in human cancer cell lines and that the Shg1 domain of BOD1L plays an indispensable role in human MOLM-13 leukemia cell line. BOD1L knockout increases apoptosis and reduces cell cycle. The strong BOD1L dependency in AML cells was also confirmed using a mouse MLL-r leukemia model in vitro and in vivo. SETD1A catalytic domain mutant AML cells still responded to the BOD1L sgRNAs that suggests the role of BOD1L is independent from the SETD1A catalytic function. Importantly, BOD1L knockout mimics the transcriptional profiles of SETD1A knockout cells and reduces the expression of genes in DNA damage response and heme biosynthesis. BOD1L loss immediately reduces SETD1A distribution on chromatin and increased the NELFE and RNA polymerase II signals at transcriptional start sites. These results show that BOD1L is an essential component of the non-catalytic SETD1A function in transcriptional pause release.
We also performed an immunoprecipitation assay using tagged constructs to examine the interaction between BOD1L and SETD1A. Our data indicate that SETD1A associates with BOD1L through the FLOS domain, especially in the C-terminal region. In addition, we found that the loop structure in the Shg1 domain of BOD1L is associated with the nonenzymatic domain of SETD1A. A split luciferase complementation assay reveals that the BOD1L Shg1 domain and SETD1A FLOS domain interact. To demonstrate the role of BOD1L chromatin interaction, we enforced localization of the Shg1 domain fragment at a silent gene locus and it successfully induced ectopic SETD1A recruitment to chromatin and formation of the COMPASS complex. However, we observed neither induced H3K4me3 modification nor RNA polymerase II recruitment. Taken together, while the BOD1L-SETD1A complex is not sufficient to act as a pioneer complex for active transcription, our study identified that BOD1L facilitates chromatin binding of SETD1A through the Shg1-FLOS domain interaction and then regulates transcriptional pause release, and that this interaction is a potential therapeutic opportunity for SETD1A-targeting therapy.
Obtaining M Protein Immune Reconstitution As Soon As Possible after Tandem Autologous Hematopoietic Stem Cell Transplantation Improves the Prognosis of Patients with Newly Diagnosis Multiple Myeloma
Authors: Zhu Huihui , Li Juan 
Published: December 2023

Objective: In the era of new drug therapy, autologous hematopoietic stem cell transplantation after induction therapy is the standard of care for patients with multiple myeloma, and Tandem autologous hematopoietic stem cell transplantation is a treatment option to improve the prognosis of patients with high-risk cytogenetics, and obtaining M protein immune reconstitution as soon as possible after double transplantation can further improve the survival of such patients.
METHODS: A total of 12 patients with newly diagnosed multiple myeloma diagnosed from June 1, 2019 to April 30, 2021 at the First Affiliated Hospital of Sun Yat-sen University were included, and all patients underwent tandem autologous hematopoietic stem cell transplantation after induction therapy containing bortezomib, and the prognostic survival of patients who obtained M-protein reconstitution after transplantation was analyzed
Results: 58.3% (7/12) of patients obtained M protein immune reconstitution after Tandem transplantation, the most common type of M protein was IgG-type M protein, the median time to obtain M protein immune reconstitution was 3 months (2-9 months) after Tandem transplantation, the median duration of reconstitution was 3 months (3-6 months), and all patients were R-ISS stage II-III, 83.3% (10/12) of patients had high-risk cytogenetics, all patients achieved at least VGPR efficacy after transplantation, with a higher CR rate in the M protein immune reconstitution group (71.4% vs 60.0%, P=0.679), although not statistically significant, and a median survival time of 2 years in the immune reconstitution group
CONCLUSION: Tandem transplantation is a treatment option to improve prognosis in patients with high-risk cytogenetic multiple myeloma, and patients who received M protein immune reconstitution after Tandem transplantation significantly improved survival time.
Impact of Psychiatric Comorbidity on Readmissions of Sickle Cell Disease -a Nationwide Readmissions Database Study
Authors: Kamal Syeda Ashna Fatima , Jhu Joshua , Maiocco Giuseppe , Prakash Vivek , Hussain Mohammad Junaid , Azhar Waqas , Agarwal Ishan , Bloch Evan , Tobian Aaron , Goel Ruchika 
Published: December 2023

Introduction:
While advances in the management of sickle cell disease (SCD) treatment have improved outcomes, readmission rates among patients remain a significant concern. A previous study with the National Readmission Database (NRD) 2016 found that alcohol use, tobacco use, opoid use ,substance use and depression were associated with SCD readmission even though the general rate of readmission has decreased over the years. This study aims to update the literature, and further determine the predictors associated with increased readmission among individuals with SCD.
Methods:
Using the Nationwide Readmissions Database (NRD), we evaluated readmissions for SCD for the year 2016-2020. On the basis of International Classification of Diseases, TenthRevision, Clinical Modification (ICD-10-CM) codes, we identified SCD hospitalizations (D57.0, D57.1, D57.2, D57.4, D57.8), and comorbid conditions. Usingamultivariateregressionanalysis,weestimatedtheindependent predictors of 30-day readmissions of SCD. We used STATA® Version 18.0 Software (STATACORP, TEXAS, USA) for analysis. The p-value was set at p &lt; 0.05 for statistical significance.
Results:
A total of 262,571 index admissions for adult patients with a primary diagnosis of SCD were admitted within the study period; 61,687 patients (23.6%) were readmitted within 30 days. A total of 886 and 105 deaths were reported respectively among index admissions and readmissions. Compared to index admissions, readmissions had decreased THC of 2147 U.S. dollars (95%CI: -2678 - -1615), while we found no significant change in the LOS between index admissions and readmissions. Common causes of increased rate of readmissions were SCD with mood disorder (HR=1.15, 95%CI: 1.11-1.20) , anxiety disorder (HR= 1.16, 95%CI: 1.11-1.20) and opioid use (HR=1.42, 95%CI: 1.35-1.50). Conditions associated with lower rates of readmission are Alcohol use disorder (HR 0.76, 95%CI: 0.62-0.94) and cannabis use ( HR=0.94, 95%CI: 0.88-0.99).
Discussion:
Our findings suggest that among individuals admitted with a primary diagnosis of SCD, having concurrent mood and anxiety disorders, and opioid use disorder increases rates of readmission. Interestingly, we observed that alcohol use disorder and cannabis use was associated with lower rates of readmission in SCD patients. Optimizing the comorbid conditions in patients with SCD may reduce readmission rates. However, further studies are required to establish the relationship between psychiatric comorbidity and healthcare resources utilization among SCD patients.
Integrative Analysis of the Tumor and Microenvironment to Model the Molecular Heterogeneity Underlying the Response to Cevostamab in Relapsed/Refractory Multiple Myeloma
Authors: Hamidi Habib , Nakamura Rin , Roy Sumi , Rajasekaran Kamalakannan , Diaz Giovanni , Dos Santos Cedric , Sumiyoshi Teiko 
Published: December 2023

Background: Cevostamab is an FcRH5xCD3 bispecific antibody that facilitates T-cell directed killing of myeloma cells and has shown promising activity and a favorable safety profile as monotherapy in patients with relapsed/refractory multiple myeloma (RRMM) in the ongoing Phase I GO39775 trial (NCT03275103; Trudel et al. ASH 2021). We performed an integrative analysis of peripheral blood (PB) and bone marrow aspirate (BMA) samples collected at baseline from patients in GO39775 to understand the heterogeneity of patients with RRMM and potential correlations with clinical outcome.
Methods: PB and BMA samples were collected at baseline from 100 patients in GO39775. Patients who had less than 25% missingness in any data layer were selected from the single-step (3.6/90-252mg dose levels [n=49] and 3.6/90mg tocilizumab premedication group [n=14; Trudel et al. ASH 2022]) and double-step (0.3-1.2/3.6-7.2/60-160mg dose levels [n=37]) dose-escalation and dose-expansion cohorts. To characterize immune cells, samples were profiled at a central laboratory by 8-color flow cytometry. Cytokine profiling was performed on baseline plasma samples via electrochemiluminescence and digital ELISA. Serum B-cell maturation antigen (sBCMA) levels were quantified using hybrid immunoaffinity capture by liquid chromatography with tandem mass spectrometry. For the unbiased integrative analysis, a Similarity Network Fusion algorithm was applied to preprocessed flow cytometry data from PB and BMA samples, and to baseline characteristics including demographics, prior therapies, and selected clinical laboratory analytes. Data were imputed in samples with less than 25% missingness using a random forest algorithm.
Results: Initial findings from unsupervised machine learning-based integrative clustering analysis of baseline samples from multiple immunological and clinical data types revealed three patient subpopulations with unique biological features, illustrating the molecular heterogeneity of patients with RRMM. Each cluster was characterized by distinct patterns of immune cell proportions and activation states. Interestingly, these immunologically defined clusters also corresponded to clinical outcomes. Cluster 1 had the strongest response to cevostamab, followed by Cluster 2 and Cluster 3.
Conclusions: Our novel, unbiased, machine learning, integrative clustering approach not only revealed unique molecular subtypes that illustrate the heterogeneity of patients with RRMM, but also identified immunological features associated with potentially reduced response to cevostamab therapy, which could provide direction for future research.
TRPM8 Contributes to Early Temperature-Induced Platelet Activation
Authors: Stratiievska Anastasiia , Filippova Olga , Ozpolat Hasan Tahsin , Byrne Daire , Bailey S. Lawrence , Mollica Molly , Harris Jeffrey , Esancy Kali , Daka Ajay , Sniadecki Nathan , Lopez Jose A. , Stolla Moritz 
Published: December 2023

Background: Like sensory neurons, platelets are activated by a decrease in temperature. However, the molecular mechanism of this temperature-sensing ability is unknown. Platelet activation by temperature could contribute to numerous clinical observations, most importantly to the well-known reduced lifespan of ex vivo-stored platelets for transfusion. In this study, we sought to dissect the molecular basis of the cold-induced platelet activation response and specifically, evaluate the role of the thermosensitive ion channel transient receptor potential cation channel subfamily member 8 (TRPM8) in platelets and their precursor cells.
Methods: We tested for the presence of TRPM8 on the megakaryocytic cell line MEG-01 and human platelets by immunoblotting, confocal microscopy, and imaging flow cytometry. The effect of TRPM8 on platelets was evaluated using the commercially available TRPM8 inhibitor PF-05105679. In addition, we used TRPM8 agonists such as menthol, WS-12, and icilin. Platelet shape change and αIIbβ3 integrin activation were assessed by imaging flow cytometry and conventional flow cytometry. We tested for platelet aggregation using light transmission aggregometry and for intracellular calcium by reading fluorescence on a plate reader after loading platelets with Fura-2-AM. Calcium release in response to temperature decrease was assessed after loading platelets or TRPM8-transfected HEK293T/17 and reading fluorescence in a Real-Time PCR Detection System.
Results: We detected TRPM8 mRNA and protein in MEG-01 cells and platelets but there was a remarkable variability among donors. Further evidence for TRPM8's presence in platelets came from the fact that inhibitors of TRPM8 prevented early temperature-induced platelet activation events, such as αIIbβ3 integrin activation and shape change. Unlike temperature changes, chemical agonists of TRPM8 did not seem to have an acute effect on platelets. Platelets exposed to below-normal body temperature displayed a cytosolic calcium increase, but this was independent of TRPM8 and entirely dependent on the calcium release from the endoplasmic reticulum.
Conclusion: We found evidence for TRPM8 expression in platelets but the expression varies greatly between individuals and is of unclear physiologic significance. Our study suggests that the cold response of platelets is complex, and TRPM8 appears to play a calcium-independent role in the early temperature-induced activation of platelets, while other mechanisms likely contribute to later stages of temperature-mediated platelet response. Because of the high interindividual variability of TRPM8 expression, a population-based approach should be the focus of future studies.
Integrative Genomic and Transcriptomic Analysis Reveals Genetic Alterations Associated with the Early Progression of Follicular Lymphoma
Authors: Gao Fenghua , Liu Hengqi , Wang Xianhuo , Yao Yixin , Zhang Huilai 
Published: December 2023

Background Follicular lymphoma (FL), the most common indolent lymphoma, is a clinically and genetically heterogeneous disease. However, the prognostic value of driver gene mutations and copy number alterations has not been systematically assessed.
Patients and Methods Here, we analyzed clinical-biological features of 415 FL patients to identify variables associated with disease within 24 months of first-line therapy (POD24). In addition, we applied whole exome sequencing (WES) to identify genomic alterations that predict POD24 based on 102 FL patients. Furthermore, we characterized the cellular and molecular heterogeneity within and across patients through bulk RNA sequencing and single-cell RNA sequencing.
ResultsPOD24 occurred in 21% of evaluable FL patients. To further examine the effect of POD24 on OS, we used a 24-month landmark approach for Kaplan-Meier curve analysis. As expected, POD24 was related to poor OS, and the 3- and 5-year survival probabilities of patients in whom the disease progressed within the first 24 months were 89.2% (95% CI, 84.5-93.9) and 78.6% (95% CI, 70.4-86.8), respectively, compared with 98.5% (95% CI, 97.8-99.2) and 96.2% (95% CI, 95.0-97.4) in patients who were progression free at 24 months, respectively. Moreover, patients without progression at 24 months were more likely to exhibit a CR to front-line treatment (54% vs. 35%, P = 0.001) compared to the POD24 cohort. Patients with B symptoms, elevated lactate dehydrogenase and β2-microglobulin levels, unfavorable baseline haemoglobin levels, advanced stage, and high-risk FL International Prognostic Index (FLIPI) scores had an increased risk of POD24, with FLIPI being the most important factor in logistic regression. HIST1H1D, known as a driver mutation, was correlated with POD24. Gains of 6q22.2 ( HIST1H1D) and 18q21.33 ( BCL2) and loss of 1p36.13 ( NBPF1) predicted POD24 independent of FLIPI. Integration of the four variants led to the identification of 76% of POD24 patients. Gene expression profiling of FL samples showed that the POD24 cohort was significantly enriched in the inflammatory response (mediated by interferon and tumor necrosis factor), cell cycle regulation (transcription, replication and proliferation) sets and PI3K-AKT-mTOR signaling. This result was further validated with transcriptome-wide information provided by RNA-seq at single-cell resolution.
ConclusionOur study, performed on a large cohort of FL patients, highlights the importance of distinctive genetic alterations and gene expression relevant to disease diagnosis and early progression.
Epigenetic Modulation Enhances the Therapeutic Potential of All-Trans Retinoic Acid in Acute Myeloid Leukemia
Authors: Szymanski Lukasz , Skopek Rafal , Palusinska Malgorzata , Maslinska-Gromadka Karolina , Kraj Leszek , Schenk Tino , Zelent Arthur 
Published: December 2023

Epigenetic dysregulation has been strongly associated with the development and progression of acute myeloid leukemia (AML). While all-trans retinoic acid (ATRA), a derivative of vitamin A, has demonstrated significant anti-cancer effects in acute promyelocytic leukemia (APL-AML), its clinical efficacy in non-APL AMLs has been limited. This limited response can be attributed, in part, to the epigenetic silencing of genes targeted by or involved in the ATRA pathway, rendering them unresponsive to the drug. Consequently, our research aims to overcome the epigenetic barriers in AML by combining ATRA with small molecules that possess epigenetic modulating properties.
To investigate the activation of the retinoic acid pathway in response to ATRA and a library of over 650 small molecules with epigenetic activity, we transduced HEK-293 cells with the p-GreenFire-RARE-Tk-Luc reporter construct. Through the screening process, we have identified 11 compounds that show promise as potential candidates for combination therapy with ATRA in non-APL AML. Notably, when combined with ATRA, two specific compounds, a dual PI3K HDAC inhibitor, and a pan-PKC inhibitor, demonstrated a significant 4-5 fold increase in RARE activity, indicating a synergistic effect.
To determine the impact of selected compounds on the functional level, we evaluated the viability, differentiation, and phosphorylation status of ERK1/2, AKT1, MAPK9, p38, and MAPK9 in various cell lines, including HL-60, KG1a, BMNC, and primary MSC and AML cells. The dual PI3K HDAC inhibitor and a pan-PKC inhibitor were noncytotoxic to HL60, BMNC, and primary MSC. Interestingly, dual PI3K HDAC inhibitor with and without ATRA reduced the viability of KG1α by more than 95%. Moreover, dual PI3K HDAC inhibitor and a pan-PKC inhibitor, when combined with ATRA, lead to a 2-3 fold increase in the differentiation of HL60 cells and a 2-4 fold increase in the differentiation of AML cells ex vivo compared to ATRA in combination with the LSD1 inhibitor TCP (treatment control protocol) and untreated cells from AML subtypes M1, M2, and M4. PI3K HDAC inhibitor combined with ATRA significantly reduced p-MAPK and p-p38 levels while increasing the phosphorylation of p53 in HL-60 cells. Furthermore, RNA sequencing and chromatin profiling by Cleavage Under Targets and Tagmentation (CUT&Tag) were performed to gain additional insights into the molecular mechanisms involved.
Based on obtained results, the combination of ATRA with specific dual PI3K HDAC and pan-PKC inhibitors holds promise as a potential therapeutic approach for AML. Nevertheless, further investigations, including studies utilizing patient-derived xenograft models, are warranted to validate the efficacy and feasibility of this proposed treatment strategy.