bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitochondrial Fission Protein Drp1 Regulates Platelet Function
Authors: Jacob Shancy , Tistao Marina , Ajanel Gomez Abigail , Denorme Frederik , Kosaka Yasuhiro , Manne Bhanu Kanth , Guo Li , Campbell Robert A. , Rondina Matthew T. , Rowley Jesse W 
Published: December 2023

Background: Mitochondria in platelets contribute to platelet function and are altered by diseases that involve dysregulated hemostasis or thrombosis. Mitochondrial integrity, governed by its size, number and distribution is modulated by fusion and fission proteins. Pharmacological inhibition of the mitochondrial fission protein Dynamin-related protein 1 (Drp1) has been shown to inhibit granule release in human platelets and impair thrombus formation in a murine model of thrombosis. However, the mitochondrial roles for Drp1 in platelet function are still largely unknown.
Objective: To determine the mitochondrial roles of Drp1 in regulating platelet function.
Methods: PF4-Cre mediated MK/platelet specific Drp1 null mice (Drp1 -/-) were used. Platelet morphology in Drp1 -/- and wild type (WT) platelets was analyzed by confocal microscopy. Procoagulant platelet formation (PS +ve platelets) after thrombin and the GPVI agonist convulxin (THR+CVX) stimulation was measured using Annexin V staining. Mitochondrial potential (ΔΨm) and mass at baseline and after stimulation was measured using TMRM and mitotracker green. Washed platelet activation in WT and Drp1 -/- platelets in response to convulxin was measured by flow cytometry. Platelet cytoplasmic calcium transients were measured using FURA-2AM after stimulation with THR+CVX. Phosphorylation of Drp1 (pDrp1 S616) in washed WT platelets in response to dual agonist THR+CVX was measured by western blotting.
Results: Drp1 -/- platelets were bigger in size than WT platelets as measured by microscopy and had increased mitochondrial mass as determined by flow cytometry. Absence of Drp1 reduced activation of the αIIb/β3 fibrinogen binding receptor (P=0.035; n=5-6 per group) and reduced alpha granule release (P=0.025; n=5-6 per group) in response to CVX.Dual agonist stimulation resulted in reduced PS +ve platelets in Drp1 -/- compared to WT platelets (P=0.0035; n=7 per group). Since depolarization precedes PS exposure, we measured ΔΨm using TMRM in resting and dual agonist stimulated WT and Drp1 -/- platelets. No difference in ΔΨm was observed in resting Drp1 -/- vs WT platelets whereas, stimulated Drp1 -/- platelets exhibited significantly higher ΔΨm (P=0.038; n=4 per group) than stimulated WT platelets. Interestingly, in response to dual agonists, Drp1 -/- platelets also showed a significant increase (P&lt;0.001) in cytoplasmic calcium transients than WT platelets. Western blot analyses of washed WT platelets stimulated with dual agonist showed phosphorylation of Drp1 at S616 (S616), indicating Drp1 activation.
Conclusion: These findings highlight a role for Drp1 in murine platelet mitochondrial function, GPVI activation, and procoagulant platelet formation.
A Prospective, Observational Study of Bleeding and Quality of Life in Patients with Glanzmann Thrombasthenia in the United Kingdom: Updated Results
Authors: Rea Catherine , York Thomas , Lorch Ulrike , Khair Kate , Pembroke Luke , Amin Jigar 
Published: December 2023

Glanzmann thrombasthenia (GT) is a rare bleeding disorder characterized by impaired platelet function. Recent studies suggest that patients with GT experience high-frequency bleeds, often access medical care, and have a significant burden of disease. There are no detailed, prospective studies characterizing bleeds and associated patient-reported impacts in GT.
We conducted a prospective diary study characterizing bleeds and associated patient-reported impacts in 30 patients with GT over 3 months. Patients record bleed events daily in a custom-designed electronic bleed diary. At approximately the same time each day, they answer the question, “Have you had a bleed?” If the answer is yes, they also include the anatomical site of the bleed. Female patients are asked to record menstrual bleeding. For each bleed reported, patients can document symptoms, treatments received, and the location where the treatment was received (e.g., at home or in the hospital). They are also asked to record the socioeconomic impacts of individual bleeds, such as missed social or leisure activities, missed work, and missed education.
The updated results confirm the high frequency of bleeds in patients with GT. Key variables will include diary completion compliance, mean monthly bleed rate (excluding menstrual bleeding), as well as detailed recordings of types and anatomical locations of bleed events. Further details will include patient reported, bleed-associated symptoms and socioeconomic impacts. In addition, a thorough description of menstrual bleeds and the impacts reported by women will be presented.
This study provides further evidence of the high frequency and significant impact of bleeds in patients with GT. These prospective data establish a direct link between bleed events and the corresponding impact on QOL (quality of life) in patients with GT. In addition, the findings of this study suggest that there is a need for new treatments for GT that can reduce the frequency of bleeds and improve the quality of life for patients.
Impact of COVID 19 on Patients with Multiple Myeloma : A National Inpatient Sample Analysis
Authors: Sanghvi Ankushi , Patel Sagar , Nanavaty Dhairya , Nadeem Ahmed 
Published: December 2023

Introduction:
Multiple myeloma (MM) is characterized by the proliferation of clonal immunoglobulins and suppression of normal immunoglobulins. These patients are susceptible to infections due to multiple factors such as hypogammaglobulinemia, impaired lymphocyte function, steroid-related immunosuppression, and neutropenia secondary to chemotherapy. There is limited data on the association of COVID-19 infection with in-hospital outcomes of MM. We hypothesize that COVID-19 infection is associated with adverse outcomes.
Methodology:
We queried the National Inpatient Sample (NIS) Database 2020 for adult (aged ≥ 18 years) hospitalizations with a primary diagnosis of MM. The cohort was subcategorized based on the presence of COVID-19 infection. The primary outcome studied was in-hospital mortality. Multiple secondary outcomes were analyzed including length of stay, cost of hospital stay, and individual organ system failures. Multivariable logistic regression was performed adjusting for patient and hospital level characteristics to evaluate outcomes. An alpha error of 0.05 was accepted for all analyses.
Results:
A total of 111,540 MM hospitalizations were included in the study, of which 2,195 (1.96%) had concomitant COVID-19 infection. The mean age was almost similar in both groups. Patients with MM and concurrent COVID-19 infection, had significantly higher in-hospital mortality [adjusted odds ratio (aOR) 6.54, 95% CI 5.25-8.20, p&lt;0.001], length of stay [aOR 4.12 (2.92-5.32), p&lt;0.001] and hospitalization cost [$54,940 ($34,688-$75,191), p&lt;0.001]. They had higher rates of cardiac arrest (2.9% vs 1.1%, p&lt;0.001), acute renal failure (48.8% vs 31.3%, p&lt;0.001), acute liver failure (2.5 % vs 1.1%, p&lt;0.001), acute respiratory failure (50.8% vs 17.3%, p&lt;0.001). They also required higher levels of care in terms of hemodialysis (14.8% vs 8.8%, p&lt;0.001), non-invasive ventilation (8.4% vs 3.3%, p&lt;0.001), and invasive ventilation (1.6 % vs 0.3%, p&lt;0.001).
Discussion:
Patients with MM who were admitted with COVID-19 had higher odds of in-hospital mortality, and developing (end-organ)complications such as cardiac arrest, respiratory failure, renal failure, and liver failure. They also had longer and costlier stays. The development of COVID-19 in patients with MM causes such poor outcomes likely due to shared endothelial dysfunction, thrombosis, and hyperinflammation. Prior studies have also shown impaired response to mRNA vaccination in this population. Thus, as COVID-19 restrictions are now at ease, increased vigilance is required in this vulnerable population. The limitations of our study are retrospective use of the administrative database with a potential of missing or inaccurate data, lack of information on specific treatments in MM patients limiting the ability to assess treatment-related outcomes, and unknown vaccination status.
Machine Learning Can Outperform Ann Arbor Staging in Predicting Survival in Patient with Diffuse Large B-Cell Lymphoma: Analysis of a Large National Cancer Database
Authors: Kumar Madhan Srinivasan , Gujju Veena , Park Ji Hwan , Hogue Debra , Naqash Abdul Rafeh , Al-Juhaishi Taha Mahdi Salih 
Published: December 2023

Introduction:
Diffuse Large B-cell Lymphoma (DLBCL) is the most common lymphoma in the world with usually an aggressive clinical course. The Ann Arbor staging system and International Prognostic Index (IPI) commonly utilized in clinical practice for risk stratification have known limitations. Machine learning (ML) has emerged as a promising tool for more comprehensive and deeper data analysis. We sought to utilize the ability of ML to predict survival in DLBCL compared to Ann Arbor staging system using a large national database.
Methodology:
We employed the ML algorithm XGBoost on the National Cancer Institute's Surveillance, Epidemiology and End Result (SEER) database to predict overall survival (OS) and the lymphoma specific survival (LSS). For prediction analysis, we transformed the survival labels into a simple Boolean format: “alive” represented as 0, “dead” as 1, and “dead (attributable to this cancer diagnosis)” also as 1. We utilized one-hot encoding to convert categorical features and variables into binary vectors. The data set was divided into two parts: training (80%) and test (20%). Further, we split the training set into the actual training set and validation set by using stratified 5-fold cross validation. Hyper-parameter optimization was done within the validation set. A broad range of attributes were utilized by the model for its prediction algorithm. To understand how each attribute contributes to predictions, we calculated its importance score in XGBoost.
Results:
A total of 64,912 patients with DLBCL were found and their data were extracted. The majority were Caucasian (78.9%) with a median age range of 60 to 69. The model was able to predict OS and LSS, with an area under the curve (AUC) of 0.89 and 0.75 (Figure 1), respectively. Factors selected by the model for survival prediction included presence or absence of B-symptoms, treatment status, and disease stage. For OS and LSS, the model found B symptoms to be the highest contributing factor with an importance score of 0.205 and 0.167, respectively. Other important factors incorporated by the model included age and stage IV for OS, and stage IV and clinically asymptomatic status for LSS. The least important factors were location of the primary lymphoma site and year of diagnosis (Table 1).
Conclusion:
Machine learning tools can help predict survival in patients with DLBCL and able to challenge current staging systems. Our results warrant validation in future prospective studies.
Comparison of Non-Myeloablative Conditioning Regimens Flu/Bu2, Flu/Mel 100 and Flu/TBI in Patients with AML and MDS
Authors: McKiernan Phyllis , Gelman Simon , Rowley Scott D , Kaur Sukhdeep , Cho Christina , Suh Hyung C , Boonstra Michele S , Georgantzis Addi , Baker Melissa , Einstein Amy , Donato Michele L. 
Published: December 2023

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment modality for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Non-myeloablative (NMA) conditioning regimens are used to decrease toxicity, making HSCT more tolerable and available to older patients or patients with co-morbidities. It remains unclear as to which NMA regimen leads to superior outcomes.
Methods: We retrospectively compared outcomes of 3 NMA regimens in 98 patients with AML or MDS undergoing allogeneic HSCT from January 2017 to December 2021. The 3 regimens were: Flu/Mel 100: fludarabine 40 mg/m2 days -5 to -2, melphalan 100 mg/m2 day -2; Flu/Bu2: fludarabine 30 mg/m2 days -6 to -2, busulfan 130 mg/m2 days -3 to -2; Flu/TBI: fludarabine 30 mg/m2 days -4 to -2, total body irradiation 200-300 cGY on day-1. Patients conditioned with Flu/Mel 100 or Flu/Bu2 also received rabbit anti-thymocyte globulin 4-6 mg/kg. Graft versus host disease (GVHD) prophylaxis consisted of tacrolimus and low dose methotrexate for patients receiving Flu/Mel 100 or Flu/Bu2, and sirolimus, cyclosporine and mycophenolate mofetil for patients conditioned with Flu/TBI.
Continuous variables were compared between conditioning regimens using Pearson's Chi-squared test or Fisher's exact test. PFS and OS survival probability and survival times were estimated with Kaplan-Meyer(K-M) procedure. To compare survival distributions between conditioning regimens, a log-rank test was used. We report 24-month survival probabilities in months with corresponding 95% confidence intervals.
Results: Patient demographics were balanced between the 3 groups including age (range 54-80), gender, disease risk and cell source (Table 1). 24-month progression free survival (PFS) was not different between the groups: Flu/Mel 100 was 70% (47%-100%), Flu/Bu2 was 49% (39%-63%), and Flu/TBI was 33% (18%-61%) (p=0.3). For Flu/Mel 100 the 24-month overall survival (OS) was 70% (47%-100%), Flu/Bu2 was 53% (42%-66%), Flu/TBI was 32% (17%-61%) which was not statistically different ( p=0.3) (Figure 1). There was no difference between the 3 groups for non-relapse mortality (NRM) ( p=0.46). The incidence of all grade acute GVHD was 70% for Flu/Mel 100, 66% for Flu/Bu2 and 76% for Flu/TBI ( p=0.70). There was no difference in the incidence of chronic GVHD between the groups; Flu/Mel 100 50%, Flu/Bu2 55%, Flu/TBI 57% (p&gt;0.99).
Conclusions: All three NMA regimens were found to be statistically equivalent. NRM, PFS, OS and the incidence of acute and chronic GVHD was not statistically different between the groups. A limitation of the study is the relatively small number of patients in the Flu/Mel 100 group. Further study with a larger sample size is needed to evaluate for small differences between the regimens.
Ixazomib, Pomalidomide and Dexamethasone (IxaPD) Pan-Oral Regimen in the Treatment of Refractory and Relapsed Multiple Myeloma
Authors: Chen Miao , Fu Rong , Chen Wenming , Wang Wei , Ma Yanping , Zhuang Junling 
Published: December 2023

Aim To analyze the efficacy and safety of Ixazomib, pomalidomide and dexamethasone (IxaPD) regimen in patients with refractory and relapsed multiple myeloma（RRMM）.
Methods Clinical data of RRMM patients were collected from 5 centers in north China from Jan 2021 to Aug 2023, who were treated by IxaPD regimen for at least two courses. Response, time to next treatment and overall survival were analyzed as end points.
Results A total of 34 patients were enrolled, including 21 in multicenter real-world study and 13 in investigator initiated IxaPD trial (NCT04989140) who were naïve to ixazomib or pomalidomide with previous treatment of 1 to 3 lines. There were 18 males and 16 females with the median age 65.5 (range 41-81) years old. The median duration from diagnosis to enrollment was 31 months (range 1-117), including 23/34 (67.3%) of patients were in first relapse. Thirteen in 24 (54.2%) patients had high-risk cytogenetic abnormalities. Regarding previous history, 20.6% presented renal insufficiency, 3 cases (8.8%) had extramedullary diseases, and 5 cases (14.7%) received autologous hematopoietic stem cell transplantation. After median 5 courses (range 2-24) of IxaPD chemotherapy, the overall response rate (ORR) was 64.7%, with 47.1% VGPR or better. The median time to achieve the best response was 2 months (range 1-6). After a median follow-up of 13 months (range 2-28), 52.9% of patients progressed and the median time to next treatment was 7 months (range 3-21). The mortality rate was 17.6%, and the median overall survival was not reached. In the multivariate analysis, response to first-line induction therapy significantly affected the time to next treatment(P&lt;0.05), while age, first relapse, R-ISS stage, high-risk cytogenetics abnormalities, and renal insufficiency did not impact significantly. Neither did those factors also have significant impact on overall survival. Most of the adverse effects (AEs) were grade 1-2, mainly skin rash, peripheral neuropathy, constipation, diarrhea, edema, arthralgia, herpes zoster, and shortness of breath. Only one case of grade 3 pulmonary infection occurred.
Conclusion The pan-oral IxaPD regimen showed anticipated effect and good tolerance for RRMM patients, especially appropriate for patients achieving deep response in first-line therapy. More patients are being enrolled and update data will be reported.
Effectiveness and Safety of a Cmop±R Regimen for the Initial Treatment of Patients with NHL
Authors: Duan Yishan , You Tao , Xu Peng , Ma Xiao , Wu Depei , Huang Haiwen 
Published: December 2023

Introduction
Non-Hodgkin's lymphoma (NHL) is a globally prevalent cancer with a high mortality rate. Although advances in treatment have improved patient survival, patients with high International Prognostic Index (IPI) scores continue to face challenges. The CMOP regimen (cyclophosphamide, mitoxantrone, vincristine, and prednisone) has shown promising efficacy in peripheral T-cell lymphomas with an overall response rate of 84%, but there is a lack of evidence in other NHL subtypes. In this study, we present preliminary results of a CMOP±R (CMOP±rituximab) regimen for the initial treatment of patients with NHL. The study is registered at ClinicalTrials.gov (NCT 2300074073).
Aim
This prospective, single-arm, open-label, multicenter phase 2 clinical trial was designed to evaluate the efficacy and safety of a CMOP±R regimen including mitoxantrone hydrochloride liposome in patients with newly diagnosed NHL.
Method
Adult patients with a confirmed diagnosis of NHL (predominantly DLBCL, MZL, FL, and AITL), ECOG performance status ≤1, normal organ and bone marrow function, and at least one measurable or evaluable lesion were enrolled in this study. Patients with significant cardiac dysfunction or uncontrolled cardiovascular disease were excluded. Treatment with the CMOP±R regimen was administered every 4 weeks for up to 6 cycles until disease progression or an intolerable toxic response. The primary endpoint was the objective response rate (ORR), which was assessed by the investigators. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Adverse events were graded using NCI Common Terminology Criteria for Adverse Events (CTCAE) 5.0. The study was approved by the Institutional Ethics Committee (IRB number: 2022021).
Results
From November 26, 2022 through May 19, 2023, 17 Chinese patients with various NHL subtypes who were eligible for enrollment were treated with the CMOP±R regimen. Nine of these patients were eligible for efficacy evaluation. Results showed that 100% of evaluable patients achieved an objective response and 66.7% achieved a complete response. Hematological toxicity was the most common treatment-related adverse reaction, with leukopenia (100%) and neutropenia (100%) being the most common grade ≥3 toxic reactions.
Conclusions
The CMOP±R regimen using mitoxantrone hydrochloride liposome showed efficacy in the initial treatment of NHL with acceptable and manageable adverse effects. The role of this regimen in the treatment of NHL warrants further exploration.
RDW As a Predictor of Adverse Outcomes: A Systematic Review and Meta-Analysis of Frailty and Mortality Risk
Authors: Keesari Praneeth Reddy , Vegivinti Charan Thej Reddy , Ganampet Narendranath Reddy , Guna Sowmya Durga Subhasri , Venugopalan Sruthi , Edusa Samuel , Manaktala Pritika Singh , Palisetti Spandana , Muslehuddin Zainab , Theik Nyein Wint Yee , Salibindla Divya , Desai Rupak 
Published: December 2023

Introduction
Red cell distribution width(RDW) is a measure of variation in red blood cell size. Although not very sensitive or specific to diagnose anemia, RDW is identified as a marker of inflammation and oxidative stress. Multiple studies in recent times have evaluated its association with overall mortality, frailty, venous thromboembolism, chronic kidney disease, and liver disease. Identifying frailty and risk of mortality is crucial and may help curtail adverse health outcomes in the aging population. We conducted a systematic review and meta-analysis to identify if high RDW serves as an indicator of frailty and mortality.
Methods
We performed a comprehensive review of Pubmed, Scopus, and Google Scholar until June 2023 using appropriate keywords to identify studies evaluating the risk of frailty and mortality in patients with high RDW. Binary random-effects model was used to estimate pooled odds ratios (OR) and 95% confidence intervals (CI). Leave one out sensitivity analysis was performed. Heterogeneity was assessed using I2 statistics. A p&lt;0.05 was considered statistically significant.
Results
A total of 9 studies were included with data spreading across 9 countries. Sample size included 881 and 1180 individuals with high RDW that reported frailty and mortality as an outcome respectively, and 5919 and 4426 individuals with normal RDW that reported frailty and mortality as an outcome respectively. Unadjusted odds for frailty were 2.10 (95% CI, 1.78 - 2.47; p-value &lt; 0.01) with heterogeneity of 0%(I2) whereas adjusted odds were 2.257 (95% CI, 1.510 - 3.373; p-value &lt; 0.001) and heterogeneity of 0%(I2). Similarly, unadjusted odds for mortality were 3.30 (95% CI, 2.21- 4.94; p-value &lt; 0.01) with heterogeneity of 75.16%(I2) and adjusted odds for mortality were 2.75 (95% CI, 1.24 - 6.08; p-value 0.01) with heterogeneity of 79.8%(I2). Sensitivity analysis using leave one out method demonstrated similar results.
Conclusion
This study concludes that there is a significantly higher risk of frailty (125%) and mortality (175%) in individuals with high RDW. RDW is a readily available and a cost effective tool. Consequently, there is a need for additional research to investigate the potential of RDW as a predictor for morbidity and mortality in various settings, such as patients undergoing targeted interventions, pre-procedural assessments, and in specific disease populations.