bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanistic Insights into Cronobacter Sakazakii-Induced Neonatal Meningitis Via TLR4-NLRP3-Mediated Pyroptosis Pathway
Authors: Chen Zhenhui , Guo Xiaotong , Yu Lu , Shan Jiamin , Daixuan Zhou , Fan Hongying 
Published: December 2024

Background: Cronobacter sakazakii (C. sakazakii) is a Gram-negative pathogen that invades the gastrointestinal tract and spreads hematogenously, leading to bacterial meningitis in premature and low-birth-weight neonates, posing a significant threat to neonatal health. However, the exact mechanisms by which C. sakazakii breaches the blood-brain barrier (BBB) and induces inflammation remain poorly understood. This study aims to elucidate the signaling pathways underlying C. sakazakii-induced neonatal meningitis using in vitro and in vivo models.
Methods: We utilized human brain microvascular endothelial cells (HBMECs), BV2 microglia cells, C57BL/6 neonatal mice, and NLRP3-/- mice to establish models of C. sakazakii-induced meningitis. In vitro assays comprised cell adhesion and invasion experiments, transmembrane resistance measurements, immunofluorescence to assess tight junctions, flow cytometry to evaluate HBMEC cell viability, and Western blot to examine changes in pyroptosis-related proteins in BV2 cells. In vivo experiments involved assessing C. sakazakii penetration through the BBB by cerebrospinal fluid (CSF) plating, immunohistochemistry for Neun protein expression in brain tissue, and Western blot for changes in pyroptosis-related proteins in brain tissue.
Results: Our in vitro findings demonstrated that C. sakazakii adheres to and invades HBMECs, reducing transmembrane resistance and disrupting tight junctions. This bacterial action induced pyroptosis in BV2 cells. In vivo experiments showed that C. sakazakii crosses the BBB, colonizes the CSF, and induces meningitis in neonatal mice. The mechanism proposed involves C. sakazakii-stimulated expression of TLR4 on the cell surface, activation of MyD88, and subsequent nuclear translocation of NF-κB, which induces the expression of NLRP3 inflammasome-related proteins. This leads to the activation of GSDMD, induces pyroptosis, and the subsequent release of the inflammatory cytokine IL-1β, culminating in the development of meningitis.
Conclusion: This study reveals that C. sakazakii disrupts tight junction proteins and breaches the BBB, activating the TLR4-NLRP3-mediated pyroptosis pathway in the brain. This mechanism induces pyroptosis and the release of the inflammatory cytokine IL-1β, ultimately leading to the induction of neonatal meningitis.
Heparin-PEAR1 Interaction Contributes to Platelet Activation By HIT Antibodies
Authors: Buka Richard John , Martin Eleyna , Lamerton Rachel E , Lagonotte Hugo , Rollin Jérôme , Gruel Yves , Calvert Anthony , Poles Anthony , Watson Stephen P , Nicolson Phillip LR , Montague Samantha J 
Published: December 2024

Introduction
Heparin is a negatively charged, heavily sulfated polysaccharide that is used in medicine as a highly effective anticoagulant. In about 1% of patients who receive unfractionated heparin, heparin-induced thrombocytopenia (HIT) can occur. This is a disorder characterized by an intensely prothrombotic phenotype and thrombocytopenia that typically occurs 5-10 days after heparin exposure. In HIT, heparin binds to positively charged platelet factor 4 (PF4), exposing neoepitopes on PF4 to which heparin-dependent anti-PF4 antibodies can bind. This results in immune complexes which activate platelets through the low affinity Fc receptor, FcγRIIA. Recently, heparin was shown to activate platelets by binding to platelet endothelial aggregation receptor 1 (PEAR1). We therefore hypothesized that heparin itself may have a role in platelet activation in HIT in cooperation with activation through FcγRIIA.
Methods
We assessed activation of healthy donor washed platelets (2 x 108/mL) to the HIT-like monoclonal antibody (mAb) 5B9 and HIT sera in the presence of heparin by light transmission aggregometry. Experiments were performed in the presence or absence of the PEAR1 nanobody, Nb138, which was raised against the heparin-binding domain of PEAR1.
Results
Heparin (0.5 IU/mL) but not the HIT-like mAb 5B9 (20 µg/mL) stimulated slow and sustained aggregation of washed platelets with a second, more rapid phase at ~20 min. The response to heparin was blocked by the PEAR1 nanobody, Nb138 (100 nM). In contrast, the combination of heparin and mAb 5B9 stimulated robust aggregation of washed platelets within 15 min (n=7). In 3/7 donors, the response was blocked by Nb138 and was delayed by over 30 seconds in two others. We then tested the effect of Nb138 on two HIT sera that also induce strong activation of platelets in the presence of heparin. Nb138 delayed aggregation to the first HIT serum in all 7 donors. Nb138 blocked aggregation to the second HIT serum in 4 donors and significantly delayed aggregation in 2 others.
Conclusions
The present results demonstrate that the platelet heparin receptor, PEAR1, potentiates the response to HIT-like mAb and HIT sera and that this is an important variable in diagnostic assays using HIT sera. Further studies are required to establish whether activation of PEAR1 contributes to the pathogenesis of HIT and whether this is due solely to binding of heparin to PEAR1 or to binding of heparin to PEAR1 when present in an immune complex.
Acknowledgements
RJB is supported by a British Heart Foundation Accelerator Award (AA/18/2/34218) and SJM by a British Heart Foundation Project grant (PG/23/11230). SPW holds a BHF Chair (CH03/003).
The Influence of Seasonal Variation on Patients with Pulmonary Embolism: A Four-Year Retrospective Analysis
Authors: El-Jabali Aseel , Abdullah Khaled M , Huynh Nam , Johnson Alexa , Mahmood Omar 
Published: December 2024

Rationale
The seasonal impact on pulmonary embolism (PE) remains an unexplored topic in prior literature in the United States. In this study, we explore the national inpatient sample (NIS) to determine how seasonal variation may impact such patients. We evaluated clinical outcomes such as all-cause mortality, length of stay, total charges, acute kidney injury, and myocardial infarction to enhance our understanding of its collective impact.
Methods
We analyzed data from the 2016-2019 NIS to identify patients admitted with a principal diagnosis of PE. Patients were stratified based on season. Categorical variables were compared using chi-square tests and continuous variables with independent samples t-testing. To adjust for potential confounding variables, we employed logistic and linear regression models. Confounders were selected through a univariate screen with a p value cutoff of less than 0.1. Additionally, the Charlson comorbidity index was utilized to account for the presence of comorbid conditions to gauge disease severity.
Results
In our analysis, we identified a total of 750,030 hospitalizations (weighted) with a principal diagnosis of PE as shown in Figure 1. The seasonal and monthly admission rates are outlined in Figure 2. There was a statistically significant difference in all-cause mortality (odds ratio [OR]: 1.09, p-value=0.046) during winter compared to summer. There was a statistically significant increase in acute myocardial infarction injury (odds ratio [OR]: 1.06, p-value=0.034), acute kidney injury (odds ratio [OR]: 1.05, p-value=0.044), and total charges prior to deduction (adjusted coefficient: $2,186, p-value&lt;0.001) during fall compared to spring. There was a statistically significant increase in length of stay (adjusted coefficient: 0.11 Days, p-value=0.002) and sepsis (odds ratio [OR]: 1.15, p-value=0.032) during winter compared to spring.
Conclusions
Compared to patients admitted during spring or summer, patients with PE admitted during the winter or fall were associated with a longer length of stay and higher total charges in addition to increased risk of all-cause mortality, acute myocardial infarction, acute kidney injury, and sepsis. These findings could be explained by several reasons including increased incidence of infections in winter leading to critical illness, colder temperatures increasing blood viscosity, abnormal coagulation due to platelet and coagulation factor dysfunction, and reduced mobility during winter increasing risk of venous thromboembolism. Literature reflects correlations between winter and increased cardiovascular complications which increases risk for pulmonary embolisms.
Entirely Venetoclax-Based Nonintensive Treatment Regimen for Newly Diagnosed NPM1-Mutated Acute Myeloid Leukemia in the ELN Favorable-Risk Group
Authors: Dou Xueqing , Chen Suning , Wu Depei 
Published: December 2024

The NPM1 mutation is one of the most common mutation types in acute myeloid leukemia (AML) and has shown a good response to venetoclax-based treatment. However, there are currently no prospective clinical trials for a nonintensive treatment regimen that is entirely venetoclax-based in NPM1-mutated AML. We conducted a single-arm, multicenter clinical study of venetoclax in combination with hypomethylating agents (decitabine or azacitidine) for the treatment of newly diagnosed NPM1-mutated AML in the ELN favorable risk group.
A total of 14 patients, including 9 males and 5 females, have been enrolled from 4 medical centers. The median age is 57 years (range, 30-76), and 12 patients were fit, while 2 were unfit. All the patients were diagnosed as AML according to the WHO 2022 criteria, while 11 cases were diagnosed with AML, 1 case with MDS-EB1, and 2 cases with CMML according to ELN 2022 diagnostic criteria. Twelve (85.7%) had NPM1 type A transcripts, 1 (7.1%) had type B, and 1 (7.1%) had a rare type. None of the patients had high-risk karyotypes, but 6 (42.9%) patients had recurrent MDS-related changes (MRCs).
The median follow-up time was 3.0 months (range, 0.5-25.0), with a median of 3 (range, 0-11) treatment cycles completed. All 12 patients who completed at least 1 treatment cycle achieved a CR/CRi rate of 100% after just 1 cycle. Of these patients, 9 (75%) achieved bone marrow (BM) molecular MRD-negative remission after a maximum of 4 treatment cycles. The median number of cycles to achieve molecular negativity was 2 (range, 1-4), with a median time to molecular negativity of 2 months (range, 1-7).
One patient experienced molecular relapse and had to withdraw from the cohort after 10 treatment cycles, while another patient had to discontinue due to severe infection. In general, NPM1-mutated patients in a favorable risk group who received a venetoclax-based nonintensive treatment regimen were able to achieve early BM molecular remission, though longer-term relapse outcomes remain to be seen.
Prior ASCT Has a Negative Impact on Outcomes in Relapsed/Refractory Multiple Myeloma Patients after BCMA CAR-T Therapy
Authors: Jin Chunxiang , Chen Rongrong , Fu Shan , Chang Alex H. , Huang He , Hu Yongxian 
Published: December 2024

Background
Despite the promising efficacy of BCMA CAR-T cell therapy in relapsed or refractory multiple myeloma (R/RMM), some patients relapse after initially responding to the treatment. Analyzing risk factors and proposing refined CAR-T cell therapy strategies is crucial to improving the prognosis of these patients.
Methods
From July 30, 2018, to September 27, 2023, 141 R/RMM patients who were receiving BCMA CAR-T therapy were enrolled. Logistic regression, Cox regression and competing risk analyses were employed to identify risk factors associated with the prognosis. Flow cytometry was conducted to measure the proportion of CAR-T cells within the total T cell population, monitoring the post-infusion dynamics of CAR-T cells.
Results
During the median follow-up of 20.2 months, the objective response rate (ORR) was 94.8%, with 50.7% of patients achieving a complete response (CR). The median progression free survival (PFS) was 15.2 months (95% CI: 7.6-22.8). Prior autologous stem cell transplantation (ASCT) was associated with lower CR rate (RR, 0.352 [95% CI: 0.149-0.830]; P = 0.017). Among 68 CR cases, patients with extramedullary disease (HR, 2.381 [95% CI: 1.108-5.116]; P = 0.026), and prior treatment with ASCT (HR, 3.622 [95% CI: 1.420-9.237]; P = 0.007) had higher cumulative incidences of relapse (CIR). Extramedullary disease (HR, 2.095 [95% CI: 1.310-3.349]; P = 0.002) and prior ASCT (HR, 2.272 [95% CI: 1.314-3.929]; P = 0.003) were identified as risk factors for poor PFS. Extramedullary disease (HR, 2.033 [95% CI: 1.104-3.744]; P = 0.023) was significantly associated with shortened overall survival (OS).
Further investigation into potential mechanisms revealed that, among the 136 patients with expansion peak data, the peak of CAR-T cell expansion was significantly lower in the ASCT group compared to the non-ASCT group (74.8% vs. 89.8% , P &lt; 0.001).
Conclusions
Our study found that prior ASCT and extramedullary disease serve as adverse prognostic factors in R/RMM patients undergoing BCMA CAR-T cell therapy. Research on the adverse effects of prior ASCT revealed it impaired the peak expansion of CAR-T cells in vivo. Moving forward, we will conduct an in-depth study on the mechanisms by which extramedullary disease affects CAR-T cell therapy outcomes in the near future.
Outpatient Maintenance Therapy of Venetoclax Combined with Azacitidine in Patients with Acute Myeloid Leukemia– a Real-World Retrospective Study
Authors: Nie Zi-Yuan , Ren Jinhai , Zhan Ying , Zhang Xiaolei , Li Jinao , Guo Xiaoling 
Published: December 2024

Objective: With the increasing use of venetoclax in patients with acute myeloid leukemia (AML), several social issues have also emerged. Hence, we have proactively explored home treatment and outpatient follow-up management for AML patients undergoing venetoclax-based therapy. This approach aims to maintain treatment efficacy while facilitating patients' reintegration into society and reducing the burden of frequent hospitalizations.
Methods: A retrospective analysis was conducted on clinical data from AML patients who received venetoclax combined with azacitidine maintenance therapy at the outpatient department of Hebei Medical University Second Hospital from July 2021 to May 2024.We retrospectively studied the effectiveness and safety of this regimen.
Results: A total of 31 patients were included, with 17 males (54.8%) and 14 females (45.2%), and a median age of 61 years (range 21-85). Among the patients receiving outpatient VA maintenance therapy, the median follow-up was 11.9 months (range 2-35.1 ), and the median treatment period was 6 (range 2-24) cycles. The best overall response rate (ORR) was 92.6% (25/27). Of the 25 patients achieving the best response of CR/CRi, 3 patients experienced progression during outpatient VA treatment, and 5 patients had relapse, resulting in an overall relapse rate of 25.9% (7/27). A total of 26 patients were tested for minimal residual disease (MRD) during treatment, and the optimal MRD negative rate was 65.4% (17/26). The median relapse-free survival (RFS) for MRD-positive patients was 8.7 months, while it was not reached for MRD-negative patients. The most common adverse events (AE) was hematologic, and the most common non-hematologic AE was pulmonary infection. Among the 31 patients, 245 cycles of chemotherapy were administered, with grade 4 thrombocytopenia occurring in 4/19 patients (21%), neutropenia in 11/13 patients (85%), and anemia in 9/19 patients (47%). Compared to inpatient treatment, where thrombocytopenia (85%), neutropenia (100%), and anemia (100%) were more common, these rates were significantly reduced during outpatient treatment. The infection rate during inpatient treatment was 70%, while the average infection rate during outpatient VA maintenance therapy was 7%, a statistically significant difference (P &lt; 0.05). The need for inpatient care due to infection was only 11 times.
Conclusions: Real-world data from our center indicate that venetoclax combined with azactidine is feasible for outpatient maintenance therapy. Patients who achieve MRD negativity can attain longer RFS and overall survival (OS), and both hematological and non-hematological toxicities are significantly reduced compared to inpatient treatment. Importantly, outpatient treatment of AML is more convenient and practical, allowing for broader implementation across various centers.
Prediction of Thrombosis in Polycythemia Vera：Development and Validation of a Globally Applicable “ANA Model”
Authors: Meng Qing , Zheng Yueyue , Liu Xiaohan , Liu Zhenyi , Jiang Xinwen , Ji Qingli , Hu Dongmei , Zhou Minran , Chunyan Chen , Ma Sai 
Published: December 2024

Background:
Avoiding or reducing the occurrence of thrombus is still the focus of clinical management in patients with polycythemia vera. Although the conventional stratification system of thrombosis has improved clinical diagnosis and treatment, it still needs to be further improved.
Objectives:
The aim of this study is to develop a prediction model of thrombosis for polycythemia vera that is globally applicable with inexpensive and readily available predictors.
Methods:
We collected clinical information of 213 newly diagnosed patients with polycythemia vera from Qilu Hospital of Shandong University,then we randomly divided them into a training cohort and a validation cohort.Multivariable Cox regression analyses were conducted for the identification of thrombotic risk factors and model development.
Results:
We investigated data from 213 patients with polycythemia vera who were diagnosed according to the 2016 World Health Organization (WHO) criteria to identify covariates associated with thrombosis.Multivariable analyses indicated that age ≥60 years (hazard ratio [HR] 2.48, 95% CI 1.00-6.15, P=0.049),neutrophil count &gt;8×10^9/L (HR 4.43, 95% CI 1.44-13.60, P=0.009),arterial thrombosis at or prior to diagnosis (HR 2.93, 95% CI 1.11-7.76, P =0.03) were independent risk factors of thrombosis. After assigning coefficient-weighted scores to those risk factor, a new thrombosis prediction model named “ANA model(age,neutrophil count,arterial thrombosis history-ANA)” was developed, classifying patients into low-risk and high-risk groups according to the final total score.Patients in the 2 groups had notably different thrombosis-free survival rates both in training cohort (P &lt; .001) and validation cohort (P &lt; .001). The ANA model outperformed the conventional model in discrimination power (C-statistic: 0.786 [95% CI 0.729-0.843] vs 0.759 [95% CI 0.718-0.800]).Moreover, the DCA curve of ANA model showed better net benefits compared to the conventional model especially when the threshold is between 12 .5%-50%, encouragingly, the incidence of thrombosis after polycythemia vera diagnosis is within this threshold range.
Conclusion:
This retrospective study confirmed the risk factors affecting thrombosis-free survival in PV.And the ANA model shows excellent accuracy and utility for thrombosis prediction in WHO-defined polycythemia vera.
Favorable Outcomes with Bridging Radiation Therapy Prior to Anti-CD19 Chimeric Antigen Receptor T-Cell CART in B Cell Lymphoma, a Report from Saudi Arabia
Authors: Hejab Amal , Alsuhaibani Khalid , Ahmed Syed Osman , Khafaga Yasser , Alshabanah Mohamed , Alahmari Ali , Hanbali Amr , Rasheed Walid , Alshaibani Alfadel , Chaudhri Naeem A. , Saad Ayman , Alotaibi Shaykhah , Alkhaldi Hanan , Alamer Abdullah , Alfayez Mansour , Alhayli Saud , Samarkandi Hadeel H , Elhassan Tusneem Ahmed M , Syed Farhatullah , Shaheen Marwan , Alfraih Feras Abdulaziz , Alotaibi Ahmad S. , Alsharif Fahad , Almohareb Fahad , Alzahrani Hazza A. , Aljurf Mahmoud , Elfakih Riad , Albabtain Abdulwahab 
Published: December 2024

Objective:
To analyze the outcomes of B cell Lymphoma patients who received bridging Radiation therapy (XRT) prior to anti-CD19 CART axicabtagene ciloleucel (Axi-cel).
Methods:
Retrospective review of patients with relapsed/refractory B cell lymphoma who received anti-CD19 CART axicabtagene ciloleucel (Axi-cel), since its launch in King Faisal specialist Hospital and Research Center from February 2023 until April 2024. We analyzed the outcomes of patient who did vs did not receive bridging XRT pre- CAR-T lymphodepletion and infusion.
Results:
Fifty patients received Axi-cel in our institution during the study period, of whom, 13 patients received bridging XRT. The median follow up was 7.6 months or 228.5 days (25-475). The baseline characteristics were similar between the XRT & no XRT group. Median age was 53.5 years (17-78), 30 patients (60%) were males, ECOG was 1 or less in 43 pts (86%). CART was used as a third line or beyond in 9 patients (69%) in the XRT group, vs in 22 patients (59.5%) in the no XRT group.
The ORR & CR by day +90 were both 77% in the XRT group (10 of 13 pts). In the no XRT group, day +90 ORR was 51.4% (19 pts of 37) & CR was 43.2% (16 of 37 pts). At 12 months, the estimated PFS in the XRT group was 76%, vs. 47% in no XRT group (P=0.051). At 12 months, the estimated overall survival (OS) in the XRT group was 88.9%, vs. 72.1 % in the no XRT group (p= 0.299).
The median radiation dose was 28 Gy (range 9-30). The median number of fractions was 10 fractions (range 4-17). The most frequent radiation site was the mediastinum, n=5 (38.5%), of whom, 3 patients had Primary mediastinal B Lymphoma.
In the XRT group, all 13 patients (100%) experienced Cytokine Release syndrome CRS and all were grade I/II. In the no XRT group, 33 patients (89%) had CRS with 2 pts (6%) being grade III/IV CRS. Immune effector cells associated neurotoxicity syndrome ICANS occurred in 7 patients (54%) of the XRT group and in 12 patients in the no XRT group (32.4%). Grade III/IV ICANS was reported in 3 pts (43%) vs 8 pts (66.7%) in the XRT vs no XRT groups, respectively.
Conclusion:
Bridging Radiation therapy prior to anti-CD19 CART Axi-cel appears to be a promising strategy to improve outcomes. Further studies are needed to understand the interaction of XRT with CART, perhaps at the molecular level, with the potential benefit of avoiding further systemic therapy to preserve the fitness of T-cell prior to CAR-T infusion.