bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of Platelet 12-Lipoxygenase Aggravates the Severity of Sars-Cov-2 Infection
Authors: Andrade Ana Claudia , Lacasse Emile , Dubuc Isabelle , Gudimard Leslie , Puhm Florian , Queiroz Celso , Allaeys Isabelle , Prunier Julien , Dumais Élizabeth , Flamand Nicolas , Droit Arnaud , Boilard Eric , Flamand Louis 
Published: December 2023

Uncontrolled inflammation and dysregulation of platelet activity, leading to venous thromboembolic events are hallmark pathological findings of severe COVID-19. Considering that 12-lipoxygenase (12-LOX) is a key enzyme regulating platelet activity, we investigated its contribution during SARS-CoV-2 infection.
To examine the role of platelet-type 12-LOX, we performed intranasal infections of angiotensin-converting enzyme 2 transgenic mice (K18-hACE2) and K18-hACE2 knockout mice for the Alox12 gene, which encodes the platelet 12-LOX enzyme, using 500 TCID50 of the SARS-CoV-2 Delta strain. Notably, Alox12 knockout mice exhibited more severe disease and higher lethality. To decipher the drivers of this increased severity, we evaluated pulmonary tissue inflammation in mice. The Alox12 knockout mice showed elevated levels of central inflammatory cytokines/chemokines such as IFN-α, IFN-γ, IL-6, CCL-3, CCL-2, CCL-4, CXCL-1, CXCL-9 measured by Luminex multiplex assays. These results were corroborated by histopathological analysis, indicating a higher inflammatory score on the third and fifth day post-infection. Despite 12-LOX's role in platelet activation, we found no signs of higher coagulation processes in the pulmonary tissues of knockout animals, as evidenced by histopathology and preliminary transcriptome analysis of lung tissue.
Furthermore, we investigated the effect of 12-LOX loss on whole blood leukocyte populations by flow cytometry throughout the infection. No significant differences in these populations were observed in the knockout animals relative to WT mice. To explore the impact of 12-LOX metabolites on pulmonary inflammation, we performed mass spectrometry analysis of the main biolipids. Our study unveiled a significant decrease in the levels of inflammatory mediators, namely 12-HETrE, PGE1, 12-HEPE, Maresin-2, 12-HETE, 15-HETE, 11-HETE, LTB4, and 12-KETE, in the lungs of Alox12 knockout mice.
Taken together, our results underscore the critical role of platelet 12-LOX in regulating pulmonary inflammation during SARS-CoV-2 infection. Loss of this enzyme disrupts even more the production of inflammatory mediators following infection, exacerbating disease severity. Our findings highlight the relevance of platelet 12-LOX activity in the regulation of pulmonary inflammation after SARS-CoV-2 infection, shedding light on potential therapeutic targets.
Autologous Hematopoietic Stem Cell Transplantation May Overcome the Adverse Impact of IKZF1 on the Prognosis of B-ALL in CR1 with No Detectable Minimal Residual Disease
Authors: Wang Jiali , Zhang Rongli , Jiang Erlie 
Published: December 2023

Purpose: Ikaros family zinc finger 1 (IKZF1) mutation may serve as a poor prognostic factor in B-cell acute lymphoblastic leukemia (B-ALL). This study explored the impact of autologous hematopoietic stem cell transplantation (auto-HSCT) on the outcome of B-ALL patients with IKZF1 alterations.
Methods: we detected the IKZF1 mutation at diagnosis in the bone marrow of adult patients with B-ALL, and analyzed the clinical data of these patients retrospectively.
Results: A total of 38 B-ALL patients in CR1 were enrolled in the study, including 8 recipients of auto-HSCT and 30 of allo-HSCT. The treatment efficacy was evaluated from a model stratified on the risk classification and minimal residue disease (MRD) status after three chemotherapy cycles. Auto-HSCT demonstrated comparable 3-year overall survival (OS) (75% vs. 89.4%, p = 0.893) and leukemia-free survival rates (80% vs. 75.3%, p = 0.471) compared to allo-HSCT for patients with negative MRD (Figure 1). There was also no significant difference on 3-year relapse rate between auto-HSCT and allo-HSCT groups (20% vs. 26%, p=0.394).
Conclusion: Auto-HSCT may be an attractive treatment for B-ALL patients of IKZF1 mutation with negative MRD after three chemotherapy cycles. The adverse impact of IKZF1 on prognosis may be overcome by auto-HSCT.
Real-World Safety and Clinical Response of Flumatinib in the Treatment of Chronic Myeloid Leukemia: A Retrospective Study
Authors: Chunyan Chen 
Published: December 2023

Objective: The objective of this retrospective study was to assess the effectiveness and safety of flumatinib in the treatment of chronic phase chronic myeloid leukemia (CML) in real-world settings.
Methods: A total of 61 patients who received flumatinib as first-line therapy were compared with 92 patients who received first-line imatinib therapy. Furthermore, the 58 patients who received flumatinib as post-line therapy were divided into two groups based on the timing of switching to flumatinib: an early conversion group (n=18) and a late conversion group (n=40). The molecular responses and outcomes were assessed at multiple time points (3, 6, 9, and 12 months) during the treatment of flumatinib, along with the observation of adverse reactions.
Results: In comparison to imatinib, the use of flumatinib as a first-line therapy demonstrated statistically significant increases in early molecular response (EMR), major molecular response (MMR), and deep molecular response (DMR) at various milestones (p&lt;0.05). Additionally, the incidence of adverse events was lower in the flumatinib group, as evidenced by higher event-free survival (EFS) rates (83.6% vs. 39.1%, P=0.01) and a lower medication switching rate (90.2% vs. 31.5%, P&lt;0.001). However, there were no significant differences observed in overall survival (OS) and progression-free survival (PFS) rates between the two groups (P&gt;0.05). In the context of post-line therapy, a significant proportion of patients (72.2%) achieved EMR at 3 months, while 71.9% achieved MMR at 12 months when treated with flumatinib. Notably, the early conversion group exhibited higher rates of molecular response and demonstrated superior OS, PFS, and EFS at the 12-month mark compared to the late conversion group (P&gt;0.05). Adverse events (AEs) commonly associated with flumatinib encompassed limb discomfort, gastrointestinal reactions, and elevated transaminase levels, with thrombocytopenia being the most frequently observed hematologic AE.
Conclusion: Flumatinib exhibited notable efficacy and safety as a therapeutic option for patients with chronic phase CML, whether utilized as a first-line or post-line treatment. In comparison to imatinib, initial administration of flumatinib resulted in more profound and expeditious molecular responses. The utilization of flumatinib as a post-line therapeutic approach during the early stage of treatment exhibits a favorable influence on patient prognosis. However, no statistically significant disparity was noted when compared to the group receiving switch therapy during the late stage.
Clinical Characterization of Hepatic Light Chain Amyloidosis in the Chinese Population: A Single-Center Retrospective Analysis
Authors: Chen Chen , Yu Chenqi , Li Jing , Wang Weiguang , Wang Zhimei , Cheng Lu-Ya , Chen Fei-fei , Xu Jiadai , Xu Tianhong , Yang Yang , Wang Wenjing , Wang Pu , Liu Peng 
Published: December 2023

CONCLUSION
Hepatic light chain amyloidosis is caused by malignant plasma cells that abnormally secrete immunoglobulin light chains, which undergo a conformational change to a β-pleated sheet configuration and are deposited in the liver. The amyloid fibrils are deposited mainly in the hepatic sinusoids, the space of Disse and the walls of blood vessels. Previous autopsy studies have shown that the proportion of systemic light chain amyloidosis with liver involvement is extremely high; however, there are fewer systematic analyses of the clinical features in the Chinese population. Therefore, this study retrospectively analysed the clinical data of patients with hepatic lightchain amyloidosis in our center to further explore the clinical characteristics of this disease.
A total of 40 patients with hepatic light chain amyloidosis were included in the analysis from 2007 to 2022. Inclusion criteria were positive liver tissue biopsy or positive biopsy of other organs with alkaline phosphatase (AKP) greater than 1.5 times the upper limit of normal or total liver span &gt;15 cm in the absence of heart failure.
The median age of these patients was 58±10 years and 80% were male. Of these 40 patients, 66% had light-chain amyloidosis secondary to myeloma and the remainder had primary amyloidosis. The proportion of patients with symptoms related to liver injury as the initial clinical presentation was 33%. Symptoms included malaise, abdominal distention, or jaundice. 40% of patients with symptoms related to abnormal heart function, such as chest tightness, severe shortness of breath, and dizziness. 25% of the patients were first seen for symptoms related to impaired renal function, such as proteinuria with lower limb edema or hypourocrinia. κ-type was found in 28% of the patients and λ-type in 73%. All patients had other sites of involvement, 95% with cardiac involvement (72.9%, Mayo 2004 stage III) and 48% with renal involvement. AKP was elevated in 100% of patients, r-GT in 95%, liver enzymes in 33%, total bilirubin in 44%, and the maximum anteroposterior diameter of the right lobe of the liver was 16.6±1.7 cm (upper limit of normal was 10 cm). In this cohort of patients, 80% received a 2- to 3-drug combination regimen based on proteasome inhibitors and 5% received a 2-drug combination regimen based on melphalan, with a median survival time of 6.5±31.3 months, and patients with a normal total bilirubin level had an overall survival time 2.4 times longer than those with an elevated level (p&lt; 0.05,Figure 1).
Contrary to previous reports of hepatic light chain amyloidosis, λ light chain amyloidosis was predominant in our center; elevated total bilirubin was an independent risk factor for survival.
Adhesion of Immunoglobulins to Band3 Promotes Increased Erythrocyte Sedimentation Rate in Multiple Myeloma
Authors: Zhang Xialin , Cui Jiangxia , Bian Sicheng , Zhang Ruijuan , Li Yinghua , Chen Xiuhua , Chang Jianmei , Tan Yanhong 
Published: December 2023

An increase in ESR can be seen in approximately 85% of patients with MM [1]. Therefore, ESR is often used as one of the sensitive indicators of active MM [1]. It is now widely accepted that the increase in ESR is related to the adhesion of immunoglobulins secreted by myeloma cells to erythrocytes [2, 3]. However, this explanation is descriptive and speculative and has not been confirmed by experimental data [3].
We applied peripheral blood erythrocyte samples from MM patients and used immunofluorescence/immunoprecipitation tandem protein analysis/molecular docking to determine the molecular mechanism by which all types of MM immunoglobulins can target and adhere to erythrocyte membrane Band3.
This result, not only helps to explain the molecular mechanism of ESR acceleration in MM, but will also advance our understanding of the pathophysiologic changes that occur in ESR. At the same time, it may provide a new way to target protection of normal erythrocytes and targeted removal of erythrocyte-bound immunoglobulins.
Single-Cell RNA Sequencing Facilitates Study of Cancer Mechanisms across Pediatric Leukemias
Authors: Pushel Irina , Yoo Byunggil , Louiselle Daniel , Gibson Margaret , Gamis Alan S , August Keith J. , Flatt Terrie , Pastinen Tomi , Guest Erin M. , Farooqi Midhat S 
Published: December 2023

Leukemia is the most common pediatric cancer, diagnosed in over 3,000 children annually in the US. While the prognosis for many pediatric leukemias has significantly improved with the addition of DNA sequencing to the diagnosis and treatment selection process, the molecular mechanisms driving some cases remain inscrutable. In this study, we performed single-cell RNA sequencing on a cohort of pediatric leukemia samples (n = 72) to explore intra- and inter-patient heterogeneity across multiple types of malignancies: acute megakaryoblastic leukemia (AMKL, n = 1), acute myeloid leukemia (AML, n = 14), acute promyelocytic leukemia (APL, n = 1), B-cell acute lymphoblastic leukemia (B-ALL, n = 32), anaplastic large cell lymphoma (ALCL, n = 1), myelodysplastic syndrome (MDS, n = 1), mixed phenotype acute leukemia (MPAL, n = 2), Ph-like B-cell acute lymphoblastic leukemia (Ph-like, n = 8), and T-cell lymphoblastic leukemia (T-ALL, n = 12).
Using the 10x Chromium system, we generated single-cell RNA sequencing data for 183,321 cells from cryopreserved blood and bone marrow samples collected from patients at diagnosis (n = 65), remission (n = 3), and/or relapse (n = 4). Sequencing data were aligned to GRCh38 and counted using cellranger-6.0.1, with downstream analysis performed using Seurat 4.0.2 in R 4.0.3. Consistent with prior single-cell studies of leukemia, we observed a high degree of inter-patient heterogeneity: cancer cells from each patient showed distinct transcriptional signatures (Figure A; circled clusters indicate mature cells of each type clustering together, while other clusters correspond to leukemic cells from a single patient).
Regardless of leukemia type and cell of origin, many patient samples contained cells most transcriptionally similar to hematopoietic stem cells (HSCs; Figure B). At diagnosis, the proportion of HSCs-like cells ranged from 7% in patients with MPAL to 46% in AML. Samples collected at relapse showed a striking increase in the proportion of HSC-like cells in both B-ALL (97%, compared to 45% at diagnosis) and Ph-like (92%, compared to 16% at diagnosis). Comparative analysis of this cohort additionally revealed marker genes specific to each leukemia, reflecting the diverse cell of origin and molecular mechanisms driving each cancer, including PRDM2 and ID3 for B-ALL, PRDM16 and CSF3R for AML, as well as SKI and PTPRC for MPAL.
In this study, we use single-cell RNA sequencing of a large pediatric leukemia cohort to gain novel insights into the transcriptional drivers and heterogeneity of leukemias. Future work will extend these observations to explore transcriptional signatures associated with prognosis, both common and unique to individual cancers. In the long term, the findings from this research will facilitate improved diagnosis, patient stratification, and treatment selection for pediatric patients diagnosed with leukemia.
Outcomes Among Hospitalized Patients with Relapsing Multiple Myeloma Utilizing Palliative Care: A United States Population-Based Cohort Study
Authors: Arya Yajur , Syal Arshi , Casipit Bruce Adrian , Dourado Claudia , Mayo Ryan J , Heller Gordon 
Published: December 2023

Background
Multiple myeloma has a limiting effect on quality of life, with pain being a commonly reported symptom secondary to lytic lesions. Palliative care plays an important role in both pain management as well as addressing individualized goals of care. Newer treatment options are often implemented in patients with relapsing multiple myeloma, and have the potential to cause further treatment related adverse effects. The role of palliative care in this subgroup needs further exploration.
Methods
We utilized the 2018-2020 National Inpatient Sample (NIS) Database in conducting a retrospective cohort study. We identified hospitalized patients who have relapsing multiple myeloma and subsequently had a palliative care encounter using appropriate ICD-10 CM codes. We stratified patients based on whether they had a palliative care encounter during the hospitalization or not. A survey multivariable logistic and linear regression analysis was used to calculate adjusted odds ratios (ORs) 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 relapsing multiple myeloma with an in-patient palliative care encounter looking primarily at the in-hospital mortality, hospital LOS as well as total hospital charges.
Results
We identified a total of 16,726 hospitalized patients with relapsing multiple myeloma, of which 11.30% (1890/16,726) had an in-patient palliative care encounter. The overall in-hospital mortality among those with multiple myeloma was 9.86% (1040/16,726). Among those who had a palliative care encounter, the overall in-hospital mortality rate was significantly higher at 29.97% (566/1890) (p=&lt;0.001). Utilizing a stepwise survey multivariable logistic regression model that adjusted for patient and hospital level confounders, the inpatient palliative care encounter among hospitalized multiple myeloma patients significantly increased the risk for in-hospital mortality (adjusted OR 11.99, 95% confidence interval [CI], 8.03-17.92; p=&lt;0.001), longer hospital LOS (median LOS 7 days versus 5 days, p=&lt;0.001) and higher total hospital charges (median total hospital charge 76131 vs 48855, p=0.002)
Conclusion
Our analysis revealed a statistically significant increased risk of in-hospital mortality, hospital LOS, and total hospital charges in hospitalized patients with relapsing multiple myeloma who had a palliative care encounter. Caution should be exercised in interpreting these results as they may reflect uncontrolled and more advanced disease in patients utilizing palliative care. Further prospective studies are needed to better understand short and long-term outcomes in this patient population.
Hemolysis Induced Induction of Matrix Metalloproteinases in Sickle Cell Disease
Authors: Leslie Taylor Michelle , Pradhan-Sundd Tirthadipa 
Published: December 2023

Sickle Cell Disease (SCD) is a monogenic disorder that impacts around 100,000 people in the United
States and 20 million people worldwide. SCD is caused by a point mutation in the β-globin gene. SCD
can lead to complications, such as hemolysis, vaso-occlusion, oxidative stress, organ injury, and
erythrocyte sickling. Organ injury, specifically liver injury, is one of the main causes of mortality in SCD
patients. Hemolysis induced accumulation of hemoglobin, heme and iron acts as potent damage
associated molecular pattern (DAMP) and can cause chronic liver injury and inflammation. Previous
studies in the lab have demonstrated exacerbated injury and inflammation in SCD liver.
Chronic inflammation is known to activate matrix metalloproteinases (MMPs) which can then induce the
expression of cytokines and chemokines. In this study, we examined the role of hemolysis-induced
induction of MMPs using blood and liver samples from humanized townes SCD mouse model.
Proteomic analysis using SCD mouse blood sample revealed increased expression of 8 MMPs in
SCD mice following oxyhemoglobin treatment compared to their baseline expression. We next examined
the mRNA expression of these MMPs in the liver by doing qRT-PCR. Interestingly, two MMPs- Steap3
and Timp3, showed significant upregulation in SCD mice liver compared to the littermate control, which
positively correlated with hemolysis and the age of the mouse. Studies are currently underway to
understand the role of Steap3 and Timp3 in hemolysis-induced chronic liver injury and their potential
usage as novel biomarkers of hemolysis-induced chronic organ injury in SCD
Mortality and Prognostic Factors of Adult Patients with Acute Leukemia Admitted to the ICU: A Systematic Review
Authors: Cabral Paloma L , Sandoval-Sus Jose , Zang Zhenmei , Gallo de Moraes Alice 
Published: December 2023

Introduction: Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are the most aggressive group of hematologic malignancies (Pulte et al, 2020) and will be responsible for approximately 12,700 deaths in the U.S. during 2023(Seiger et al,2023). Improved overall survival (OS) has been observed in the past decades in both diseases, but high mortality in the Intensive Care Unit (ICU) persists, which may prevent ICU admission of those patients. We aimed to review the literature on mortality data and survival predictors of patients with acute leukemia (AL) admitted to the ICU.
Methods: Embase, Pubmed and Cochrane databases were searched for articles published from January of 2005 to December of 2020. Due to OS improvement of patients with AML, we only included studies published as of 2005 (Percival et al, 2015). Editorials, case reports and small case series were excluded.
Results: Initial search revealed 1,015 manuscripts from database and references, 650 were screened and 115 were fully assessed, for which 24 met eligibility criteria (Figure 1). A total of 13,350 patients were included in the review. Median age was 54.8 years and 57.3% of patients were male. AML represented the majority of diagnoses (98.2%).Two studies included only newly diagnosed patients, 1 study only included patients with relapsed disease and the rest (N=21) included subjects regardless of the AL status. Only 0.7% of patients had a history of hematopoietic stem cell transplantation . 81.9% of patients required mechanical ventilation, 25.3% needed renal replacement therapy, and 65.9% used vasopressors in studies data was available. Median SOFA score in the first 24h of ICU admission was 10.85 . Pooled ICU mortality and hospital mortality were 45.0% and 43.1%, respectively; 58.2% of patients were deceased at 90-day mark (Table 1). The 12 months OS was 37.3%. Higher SOFA score, need for mechanical ventilation, sepsis, vasopressor use, and age greater than 60 years were the most common predictors of ICU, hospital and 90-day mortality. Relapsed or refractory status of underlying AL was the most significant risk factor for long-term mortality.
Conclusions: Our systemic review showed that ICU mortality in patients with AL was 45.0%, which represents a survival improvement compared to prior studies on patients with hematological malignancies, where ICU mortality could be as high as 69% (Ashkenazi et al, 1986). Predictors of ICU mortality were closely related to the severity of acute illness rather than malignancy status. We acknowledge that our patient population was mostly comprised of AML cases and the majority of the original studies included a small number of patients with AL with exception of one large study (Halpern et al, 2017).